Feasibility and Short-Term Outcomes in Liver-First Approach: A Spanish Snapshot Study (the RENACI Project).

(1) Background: The liver-first approach may be indicated for colorectal cancer patients with synchronous liver metastases to whom preoperative chemotherapy opens a potential window in which liver resection may be undertaken. This study aims to present the data of feasibility and short-term outcomes in the liver-first approach. (2) Methods: A prospective observational study was performed in Spanish hospitals that had a medium/high-volume of HPB surgeries from 1 June 2019 to 31 August 2020. (3) Results: In total, 40 hospitals participated, including a total of 2288 hepatectomies, 1350 for colorectal liver metastases, 150 of them (11.1%) using the liver-first approach, 63 (42.0%) in hospitals performing <50 hepatectomies/year. The proportion of patients as ASA III was significantly higher in centers performing ≥50 hepatectomies/year (difference: 18.9%; p = 0.0213). In 81.1% of the cases, the primary tumor was in the rectum or sigmoid colon. In total, 40% of the patients underwent major hepatectomies. The surgical approach was open surgery in 87 (58.0%) patients. Resection margins were R0 in 78.5% of the patients. In total, 40 (26.7%) patients had complications after the liver resection and 36 (27.3%) had complications after the primary resection. One-hundred and thirty-two (89.3%) patients completed the therapeutic regime. (4) Conclusions: There were no differences in the surgical outcomes between the centers performing <50 and ≥50 hepatectomies/year. Further analysis evaluating factors associated with clinical outcomes and determining the best candidates for this approach will be subsequently conducted.

Locally advanced mid/low rectal cancer with synchronous resectable liver metastases: systematic review of the available strategies and outcome.

The management of patients with locally advanced mid/low rectal cancer with resectable liver metastases is complex because of the need to combine the optimal treatment of both tumors. This study aims to review the available treatment strategies and compare their outcome, focusing on radiotherapy (RT) and liver-first approach (LFA). A systematic review was performed in PubMed, Embase, and web sources including articles published between 2000 and 02/2023 and reporting mid-/long-term outcomes. Overall, twenty studies were included (n = 1837 patients). Three- and 5-year overall survival (OS) rates were 51-88% and 36-59%. Although several strategies were reported, most patients received RT (1448/1837, 79%; > 85% neoadjuvant). RT reduced the pelvic recurrence risk (5.8 vs. 13.5%, P = 0.005) but did not impact OS. Six studies analyzed LFA (n = 307 patients). LFA had a completion rate similar to the rectum-first approach (RFA, 81% vs. 79%) but the interval strategy-an LFA variant with liver surgery in the interval between radiotherapy and rectal surgery-had a better completion rate than standard LFA (liver surgery/radiotherapy/rectal surgery, 92% vs. 75%, P = 0.011) and RFA (79%, P = 0.048). Across all series, LFA achieved the best survival rates, and in one paper it led to a survival advantage in patients with multiple metastases. In conclusion, different strategies can be adopted, but RT should be included to decrease the pelvic recurrence risk. LFA should be considered, especially in patients with high hepatic tumor burden, and RT before liver surgery (interval strategy) could maximize its completion rate.

Clinical outcomes of the liver-first approach in the management of synchronous colorectal liver metastases: a retrospective study

Introduction: Almost 25% of colorectal cancer (CRC) patients have synchronous colorectal liver metastasis (SCLM) coinciding with the disease diagnosis. Liver-first approach for the treatment of SCLM involves neoadjuvant chemotherapy, subsequent liver resection, and then primary tumor resection. This strategy is adopted as the prognosis of the disease depends mainly on the metastases, not the primary tumor. This study aims to evaluate the feasibility of the liver-first approach and clinical prognosis in managing SCLM. Materials and Methods: This retrospective study included 25 patients with SCLM from July 2015 to July 2020. All patients were subjected to a liver-first approach with an "intention-to-treat" approach. Follow-up was planned for at least 3 years. Data were collected from the hospital records and included survival rates and univariate analyses of the prognostic factors, such as gender, age, and number of chemotherapy cycles to evaluate their effect on the survival probability. Results: Nineteen patients completed the treatment paradigm. Long-term outcomes reported a median overall survival (OS) of 32 months. One-year and 3-year survival probabilities were 89.5% and 42.1%, respectively. The median disease-free survival was 13 months. The number of metastatic lesions, unilobar versus bilobar disease, and the frequency of administered chemotherapy cycles significantly affected survival (p < 0.05). Seven patients (36.84%) remained disease free (no recurrence) while 2 patients (10.53%) survived with recurrence. The overall mortality included 10 deaths (52.63%) due to recurrence. Conclusion: Synchronous colorectal liver metastasis treated with the liver-first approach achieved a notable overall advantage. However, the recurrence rate remained relatively high. (AU)

Long-term results of liver-first approach strategy in patients with advanced synchronous liver metastases from colorectal cancer.

BACKGROUND: The "liver-first" approach (LFA) is a strategy indicated for advanced synchronous liver metastases (ASLM) from colorectal cancer (CRC). Includes neoadjuvant chemotherapy, resection of the ASLM followed by CRC resection. METHODS: Retrospective descriptive analysis from a prospective database of hepatectomies from liver metastases (LM) from CRC in two centers. Between 2007-2019, 88 patients with CRC-ASLM were included in a LFA scheme. Bilobar (LM) was present in 65.9%, the mean number of lesions was 5.5 and mean size 42.7 mm. Response to treatment was assessed by RECIST criteria. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier survival curves. RESULTS: Seventy-five of 88 patients (85.2%) completed the LFA. RECIST evaluation showed partial response in 75.7% and stable disease in 22.8%. Severe morbidity rate (Clavien-Dindo ≥ IIIA) after liver and colorectal surgery was present in 29.4% and 9.3%, respectively. There was no 90-day postoperative mortality in both liver and colorectal surgeries. Recurrence rate was 76%, being the liver the most frequent site, followed by the pulmonary. From the total number of recurrences (106) in 56 patients, surgical with chemotherapy rescue treatment was accomplished in 34 of them (32.1%). The mean PFS was 8.5 and 5-year OS was 53%. CONCLUSIONS: In patients with CRC-ASLM the LFA allows control of the liver disease beforehand and an assessment of the tumor response to neoadjuvant chemotherapy, optimising the chance of potentially curative liver resection, which influences long-term survival.

Preoperative leukocytosis is an independent risk factor for morbidity and survival after resection of colorectal liver metastases.

BACKGROUND: Although surgical resection of colorectal liver metastases (CRLM) remains to be the only option for long term survival, traditional surgical concepts have been challenged by the introduction of the liver first approach or neoadjuvant chemotherapy in resectable CRLM and interventional therapies. The aim of this study was to identify prognostic factors for postoperative morbidity and survival and to externally evaluate the recently introduced resection severity index (RSI), in order to optimize patient selection and treatment strategies. METHODS: This is a retrospective single centre analysis of 213 patients undergoing surgery for CRLM in curative intent between January 2010 and December 2018. RESULTS: Median follow up after liver resection was 28.56 (0.01-111.46) months. Severe postoperative complications (Clavien-Dindo ≥ IIIa) were observed in 46 (21.6%) cases. Preoperative leukocytosis (OR: 3.114, CI-95%: 1.089-8.901; p = 0.034) and operation time in minutes (OR: 1.007, CI-95%: 1.002-1.011; p = 0.002) were determined as independent risk factors. Overall survival (OS) was 46.68 months with a 5-year survival rate of 40.5%. Independent prognostic factors were preoperative leukocytosis (HR: 2.358, CI-95%: 1.170-4.752; p = 0.016), major hepatectomy (HR: 1.741, CI-95%: 1.098-2.759; p = 0.018) and low grading of the primary intestinal tumour (HR: 0.392, CI-95%: 0.231-0.667; p < 0.001). The RSI (ASAT (U/l) divided by Quick (%) multiplied by the extent of liver resection in points) was identified as independent risk factor for OS only in patients without neoadjuvant chemotherapy. CONCLUSIONS: Detection of leukocytosis in patients prior resection of CRLM was associated with increased postoperative morbidity and decreased OS and could therefore prove valuable for perioperative risk stratification.

Clinical Impact of Operative Order in Laparoscopic Simultaneous Resection for Synchronous Colorectal Liver Metastases.

Background: Curative resection for colorectal cancer and their synchronous liver metastases are increasingly performed. However, it is still unclear whether the operative order affects the surgical outcome in laparoscopic simultaneous resection of primary and liver metastatic lesions. Patients and Methods: A total of 27 patients underwent laparoscopic simultaneous resection of primary colorectal cancer and liver metastases at Kumamoto University Hospital. They were divided into two groups based on the order of resection: Colon-first (n=11) and liver-first (n=16) groups. The surgical outcomes between the two groups were retrospectively compared. Results: There was no significant difference in the perioperative surgical outcomes between the two groups except for operative blood loss, which was significantly less in the liver-first group [164 (range=5-820) versus 560 (range=95-2,016) ml, respectively] (p=0.0299). Conclusion: In the simultaneous resection of primary and liver metastatic lesions, the operative order does not affect the short-term surgical outcomes except for operative blood loss.

Surgical treatment of stage IV colorectal cancer with synchronous liver metastases: A systematic review and network meta-analysis.

BACKGROUND: The ideal treatment approach for colorectal cancer (CRC) with synchronous liver metastases (SCRLM) remains debated. We performed a network meta-analysis (NMA) comparing the 'bowel-first' approach (BFA), simultaneous resection (SIM), and the 'liver-first' approach (LFA). METHODS: A systematic search of comparative studies in CRC with SCRLM was undertaken using the Embase, PubMed, Web of Science, and CENTRAL databases. Outcome measures included postoperative complications, 30- and 90-day mortality, chemotherapy use, treatment completion rate, 3- and 5-year recurrence-free survival, and 3- and 5-year overall survival (OS). Pairwise and network meta-analysis were performed to compare strategies. Heterogeneity was assessed using the Higgins I2 statistic. RESULTS: One prospective and 43 retrospective studies reporting on 10 848 patients were included. Patients undergoing the LFA were more likely to have rectal primaries and a higher metastatic load. The SIM approach resulted in a higher risk of major morbidity and 30-day mortality. Compared to the BFA, the LFA more frequently resulted in failure to complete treatment as planned (34% versus 6%). Pairwise and network meta-analysis showed a similar 5-year OS between LFA and BFA and a more favorable 5-year OS after SIM compared to LFA (odds ratio 0.25-0.90, p = 0.02, I2 = 0%), but not compared to BFA. CONCLUSION: Despite a higher tumor load in LFA compared to BFA patients, survival was similar. A lower rate of treatment completion was observed with LFA. Uncertainty remains substantial due to imprecise estimates of treatment effects. In the absence of prospective trials, treatment of stage IV CRC patients should be individually tailored.

Effect of treatment sequence on survival in stage IV rectal cancer with synchronous and potentially resectable liver metastases.

BACKGROUND AND OBJECTIVES: The optimal treatment sequence in stage IV rectal cancer (RC) with synchronous liver metastases (SLM) remains undefined. Here, we compared outcomes between patients treated with the bowel-first approach (BFA) or the liver-first approach (LFA). METHODS: Consecutive patients diagnosed with stage IV RC with SLM and who underwent complete resection were included. Both groups were matched using propensity scores. Differences in postoperative outcome, local control, and long-term survival were studied. In addition, a decision analysis (DA) model was built using TreeAge Pro to define the approach that results in the highest treatment completion rate. RESULTS: During a 12-year period, 52 patients were identified, 21 and 31 of whom underwent the BFA and the LFA, respectively. Twenty-eight patients were matched; patients treated with the BFA experienced a longer median OS (50.0 vs 33.0 months; P = .40) and higher 5-year OS (42.9% vs 28.6%). The DA defined the BFA to be superior when the failure threshold (ie, no R0 resection, treatment discontinuation regardless of cause) for colectomy is less than 28.6%. CONCLUSIONS: In stage IV rectal cancer with SLM, either the BFA or the LFA result in similar long-term outcomes. Treatment should be tailored according to clinicopathological variables.

Resection of synchronous liver metastases between radiotherapy and definitive surgery for locally advanced rectal cancer: short-term surgical outcomes, overall survival and recurrence-free survival.

AIM: There is debate as to the correct treatment algorithm sequence for patients with locally advanced rectal cancer with liver metastases. The aim of the study was to assess safety, resectability and survival after a modified 'liver-first' approach. METHOD: This was a retrospective study of patients undergoing preoperative radiotherapy for the primary rectal tumour, followed by liver resection and, finally, resection of the primary tumour. Short-term surgical outcome, overall survival and recurrence-free survival are reported. RESULTS: Between 2009 and 2013, 45 patients underwent liver resection after preoperative radiotherapy. Thirty-four patients (76%) received neoadjuvant chemotherapy, 24 (53%) concomitant chemotherapy during radiotherapy and 17 (43%) adjuvant chemotherapy. The median time interval from the last fraction of radiotherapy to liver resection and rectal surgery was 21 (range 7-116) and 60 (range 31-156) days, respectively. Rectal resection was performed in 42 patients but was not performed in one patient with complete response and two with progressive metastatic disease. After rectal surgery three patients did not proceed to a planned second stage liver (n = 2) or lung (n = 1) resection due to progressive disease. Clavien-Dindo ≥Grade III complications developed in 6.7% after liver resection and 19% after rectal resection. The median overall survival and recurrence-free survival in the patients who completed the treatment sequence (n = 40) were 49.7 and 13.0 months, respectively. Twenty of the 30 patients who developed recurrence underwent further treatment with curative intent. CONCLUSION: The modified liver-first approach is safe and efficient in patients with locally advanced rectal cancer and allows initial control of both the primary tumour and the liver metastases.

Treatment strategies for colorectal carcinoma with synchronous liver metastases: Which way to go?

AIM: To offer an up-to-date review of all available treatment strategies for patients with synchronous colorectal liver metastases (CLM). METHODS: A comprehensive literature search was performed to identify articles related to the management of patients with synchronous CLM. A search of the electronic databases PubMed, MEDLINE, and Google Scholar was conducted in September 2014. The following search terms were used: synchronous colorectal liver metastases, surgery, stage IV colorectal cancer, liver-first approach, and up-front hepatectomy. These terms were employed in various combinations to maximize the search. Only articles written in English were included. Particular attention was devoted to studies and review articles that were published within the last six years (2009-2014). Additional searches of the cited references from primary articles were performed to further improve the review. The full texts of all relevant articles were accessed by two independent reviewers. RESULTS: Poor long-term outcomes of patients with synchronous CLM managed by a traditional treatment strategy have led to questions about the timing and sequence of possible therapeutic interventions. Thus, alternative paradigms called reverse strategies have been proposed. Presently, there are four treatment strategies available: (1) primary first approach (or traditional approach) comprises resection of the primary colorectal tumor followed by chemotherapy; subsequent liver resection is performed 3-6 mo after colorectal resection (provided that CLM are still resectable); (2) simultaneous resection of the primary colorectal tumor and CLM during a single operation presents intriguing options for a highly select group of patients, which can be associated with significant postoperative morbidity; (3) liver-first (or chemotherapy-first) approach comprises preoperative chemotherapy (3-6 cycles) followed by liver resection, adjuvant chemotherapy, and resection of the primary colorectal tumor (it is best suited for patients with asymptomatic primary tumors and initially unresectable or marginally resectable CLM); and (4) up-front hepatectomy (or "true" liver-first approach) includes liver resection followed by adjuvant chemotherapy, colorectal resection, and adjuvant chemotherapy (strategy can be offered to patients with asymptomatic primary tumors and initially resectable CLM). CONCLUSION: None of the aforementioned strategies appears inferior. It is necessary to establish individual treatment plans in multidisciplinary team meetings through careful appraisal of all strategies.

The surgical treatment of patients with colorectal cancer and liver metastases in the setting of the "liver first" approach.

A surgical resection is the only curative method in the therapy of colorectal carcinoma and liver metastases. Along with the development of interventional radiological techniques the indications for surgery widen. The number of metastases and patients age should not present a contraindication for surgical resection. However, there are still some doubts concerns what to resect first in cases of synchronous colorectal carcinoma and liver metastases and how to ensure the proper remnant liver volume in order to avoid postoperative liver failure and achieve the best results. Through this review the surgical therapy of colorectal carcinoma and liver metastases was revised in the setting of "liver-first" approach and the problem of ensuring of remnant liver volume.