Liver resection for metastatic colorectal cancer in the presence of extrahepatic disease

doi:10.1016/S1470-2045(09)70081-6

The Lancet Oncology

Volume 10, Issue 8, August 2009, Pages 801-809

https://doi.org/10.1016/S1470-2045(09)70081-6 Get rights and content

Summary

Early studies of liver resection for colorectal cancer metastases identified patients with concomitant extrahepatic disease as a group with poor outcomes. These studies concluded that the presence of extrahepatic disease should be a contraindication to resection. This contraindication has more recently been challenged. In this paper, we review the published work on metastatic colorectal cancer, pertaining to the role of surgery in patients with liver metastases and concomitant extrahepatic disease. 5-year survival after resection is worse in patients with extrahepatic disease than in patients with liver-only disease, but is similar to that seen in patients who underwent resection in the era before the use of modern chemotherapy. Recurrence occurs in most patients. There is a role for surgery in highly selected patients with single sites of extrahepatic disease, although expectations should be different than those of patients with liver-only metastases. Further studies are necessary to define the patient group best suited for resection of hepatic metastases with extrahepatic disease.

Introduction

During the 1980s and 1990s, it became generally accepted that selected patients with resectable metastatic colorectal cancer isolated to the liver could undergo hepatectomy with reasonable safety and 5-year survival beyond that reported with best supportive care or with chemotherapy. However, because of extreme selection bias, the survival benefit was questioned. Data from patients treated during this time period has since matured enough to allow us to show that surgical resection is actually curative (≥10-year disease-free survival) in at least 17% of patients.¹ As a result, hepatic resection has become the standard of care for patients with resectable metastases (figure 1). Early experience of surgery for hepatic colorectal metastases identified patients with extrahepatic disease as a group with an especially poor outcome.2, 3, 4 For this reason, the presence of extrahepatic disease was deemed a contraindication to resection.⁵ During the past 10 years, we have seen remarkable improvements in the safety and efficacy of both hepatic resection and systemic chemotherapy. Responses to systemic chemotherapy have increased from 25% to as high as 70% with use of multiagent combinations of oxaliplatin, irinotecan, fluorouracil, and leucovorin.6, 7, 8 As a result of these changes, patients with extensive bilobar, but resectable, hepatic metastases who were previously deemed unresectable, and patients with concomitant limited and resectable extrahepatic disease, are now frequently considered for surgery (figure 2).

Experience with surgery for patients with concomitant liver metastases and extrahepatic disease has slowly mounted and the previous contraindication to surgery has been challenged. Reports of results of surgical resection for patients with extrahepatic disease have been sparse until recently, and we now have a reasonable amount of published work that allows us to begin to address this controversial area. In this paper, we review studies that address the most common specific sites of extrahepatic disease considered for resection and studies that combine all sites of extrahepatic disease into the same analysis.

Section snippets

Portal lymph-node metastases

Portal lymph-node metastases in the context of hepatic metastases are the result of lymphatic drainage of the liver and, thus, represent locoregional spread of metastatic tumours, a concept termed remetastasis.⁹ This occurrence is generally accepted as evidence that metastases metastasise. Portal lymph-node metastases are well documented to be associated with poor outcomes after liver resection for metastatic colorectal cancer. In earlier studies, these outcomes were so poor that most

Pulmonary metastases

The liver and lung are the two most common sites of distant metastasis from colorectal cancer²⁴ and, therefore, many studies have been done that have assessed patients with both liver and lung metastases treated by resection. The variability in which these patients present complicates the comparison of these studies. The presentation of lung metastases must be interpreted in temporal relation to the presentation of primary and liver metastases and to the disease-free interval(s) between these

Peritoneal metastases

About 13–25% of patients with recurrent colorectal cancer develop synchronous or metachronous peritoneal metastases.35, 36 Like for hepatic metastases, there has been a gradual shift in the concept that localised peritoneal metastases do not represent systemic dissemination of disease, but rather can be a form of regional spread. This notion has served as the rationale for attempting to treat this form of spread by surgical resection and intraperitoneal chemotherapy.

There are many retrospective

Studies of combined sites of extrahepatic disease

Most modern studies that have assessed the outcomes of patients with resected liver metastases and concurrent extrahepatic disease have focused on a single site of extrahepatic disease. Few studies have combined patients with different sites of extrahepatic disease to compare their overall survival with that of patients who have liver disease only. These few studies, with the exception of one, have originated from a single centre.

The first study was of 111 patients with extrahepatic disease who

Conclusion

The role of hepatic resection for metastatic colorectal cancer has evolved from what was considered a palliative procedure to a therapy with proven curative intent. Until recently, resection for metastatic colorectal cancer has mostly been applied to patients with liver-only disease. Because the liver is such a common site of metastatic disease (the only site of metastatic disease in 30% of patients),⁵⁰ a local therapy, such as surgery, might be indicated for patients with liver-only disease

Search strategy and selection criteria

Information for this Review was obtained by searches of the Medline and PubMed databases using the following search terms: “metastatic colorectal cancer”, “hepatic colorectal metastases”, “extrahepatic disease”, “pulmonary metastatic colorectal cancer”, “peritoneal metastatic colorectal cancer”, and “stage IV colorectal cancer”. Searches of reference lists of recent review articles on subjects of surgery for metastatic colorectal cancer were also done. Only papers published in English

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Benefits of repeated resections for liver and lung metastases from colorectal cancer
2020, Asian Journal of Surgery
Citation Excerpt :
Since the liver and lung are the most common sites of metastasis, surgery might be indicated for patients with limited liver-only or lung-only metastases, while a systemic treatment might be more suitable for patients with liver metastases and extrahepatic disease or concurrent lung metastasis. However, recent studies have demonstrated that the resection of liver metastases and limited-resectable concurrent extrahepatic disease can result in higher long-term survival.13–18 Indeed, surgical managements in patients with both hepatic and pulmonary metastases has shown survival benefits that are comparable to those of hepatic or pulmonary metastasectomies.19,20
We aimed to evaluate oncological outcomes after repeat metastasectomies in patients having undergone previous resections for colorectal cancer metastases.
We examined 248 patients who underwent metastasectomies for lung and/or liver metastases at our center during a 7-year period, from January 2005 to December 2011. Recurrence-free survival 1 (RFS1) after the metastasectomy for the initial recurrence, recurrence-free survival 2 (RFS2) after the second, and recurrence-free survival 3 (RFS3) after the third repeated resections for recurrence were assessed. The overall survival (OS) rate after the first metastasectomy for the first recurrence (OS) was also assessed.
Sites of recurrence of the first metastasectomy were the liver, lung, and liver and lung in 115, 117, and 16 cases, respectively, and 133 patients had a second recurrence (133/248, 53.6%). Twenty-seven patients had a third recurrence (27/52, 51.9%), of whom 14 underwent a third metastasectomy. The 5-year and 10-year OS rates were 74.8% and 57.9%, respectively. The 1-year RFS1, RFS2, and RFS3 rates were 76%, 75%, and 39%, respectively. The hazard ratios for RFS were 1.142 and 2.590 for the first and second repeat surgeries, when compared to the first metastasectomy. The third metastasectomy showed significantly lower RFS than did the second metastasectomy.
A second metastasectomy should be considered the optimal treatment for a second recurrence. However, careful considerations should be made before performing a third metastasectomy.
Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy combined with liver resection for concurrent peritoneal and hepatic metastases of gastrointestinal and gynecological primary tumors
2019, Journal of Visceral Surgery
Cytoreductive surgery including liver resection and hyperthermic intraperitoneal chemotherapy provide survival benefit to selected patients but is associated with relevant morbidity and mortality rates. We aimed to report morbidity and mortality rates and parameters linked to increased morbidity.
Retrospective analysis of 37 patients who underwent liver resection and cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy between 2006 and 2016. From a prospectively collected database the morbidity and mortality rates and survival data were analyzed.
The mortality rate was 0% and grade III–IV morbidity was 42%. Re-operation rate was 27%. Patients with complications tended to have a higher peritoneal cancer index (16 vs. 13; P = 0.23). The performance of rectal resections was statistically significantly associated with morbidity (P = 0.02). Neither performance of other type of resections nor the hyperthermic intraperitoneal chemotherapy compound nor the completeness of cytoreduction score was associated with elevated morbidity. No complications related to liver resections were observed. Furthermore, origin of peritoneal metastases did not impact on occurrence of complications. Median overall survival for colorectal primaries was 22 months (range, 9–60 months) and 30 months (range, 12–58 months) for ovarian cancer.
Simultaneous resection of hepatic and peritoneal metastases seems to provide a survival benefit for selected patients and is associated with acceptable morbidity and mortality rates. Knowledge of patients and operative factors linked to morbidity will help to provide a strict selection process and a safer surgical procedure.
Prognostic factors value of germline and somatic brca in patients undergoing surgery for recurrent ovarian cancer with liver metastases
2019, European Journal of Surgical Oncology
To describe accurately the oncological outcomes after hepatic resection (HR) in recurrent ovarian carcinoma (ROC) evaluating clinic-pathological variables and mutational status of BRCA1/2. Although HR is considered a challenging situation in ROC patients, assessment of BRCA1/2 mutational status seems to have a relevant clinical value to guide surgical therapy.
Patients who underwent HR for ROC at the Catholic University of Rome, between June 2012 and October 2017 were included. Exclusion criteria were represented by extra-abdominal disease and presence of diffuse peritoneal carcinomatosis requiring more than 2 bowel resections. Details relative to HR were collected and BRCA analysis was performed. Predictive factors of post-HR progression free survival (PHR-PFS) were assessed by univariate analyses using Cox-proportional hazard regression models.
Thirty-four patients undewent HR within secondary cytoreductive surgery (SCS). Six patients (17.6%) presented with hepatic relapse only, while the remaining 28 patients (82.4%) had concomitant extra-hepatic disease.
In the whole series, the 3-yr PHR-PFS was 49.1% and the 3-yr post-HR overall survival was 72.9%. Univariate analysis of variables conditioning PHR-PFS showed that only BRCA mutational status played a statistically significant favourable role: the 3-yr PHR-PFS rate was 81.0% in BRCA mutated patient compared to 15.2% in wild type ones (p value: 0.001).
Our clinical analyses suggest that in ROC patients with liver disease the assessment of germline and somatic BRCA mutational status can help to select patients elegible for SCS.
Diffusion-weighted imaging and loco-regional N staging of patients with colorectal liver metastases
2019, European Journal of Surgical Oncology
Citation Excerpt :
Liver surgery in combination with perioperative chemotherapy is their standard treatment and, to date, is indicated whenever a complete resection with adequate residual liver parenchyma is feasible [3–5]. The presence of extrahepatic disease simultaneous with CLM is a negative prognostic factor but is not a contraindication to surgery [6]. Lymph-node (LN) metastases deserve some additional considerations.
Diffusion-weighted MRI (DWI) contributes to N staging of rectal cancers and diagnosis of colorectal liver metastases (CLM). About 15% of CLM patients have loco-regional lymph node (LN) metastases that impact prognosis and treatment strategy. This retrospective study is the first one to evaluate quantitative ADC measurement as a tool to identify metastatic LNs in patients with liver metastases from colorectal cancer.
All consecutive patients undergoing surgery for CLM between 2008 and 2015 were considered. Inclusion criteria were: intraoperative retrieval of at least one LN; LN ≥ 5 mm; DWI performed ≤2 months before surgery. The ADC and ADC_ratio (ADC_LN/ADC_CLM) were computed by two radiologists for all the LNs.
Among 555 patients operated for CLM, 32 met the inclusion criteria. Fifty-six LNs were analyzed and 28 were metastatic. ADC and ADC_ratio in metastatic LNs were lower than in benign LNs (ADC = 1.37 vs. 1.83 × 10⁻³ mm²/s, p < 0.001; ADC_ratio = 1.26 vs. 1.73, p < 0.001). The optimal cut-off value for ADC was 1.48 x 10^-3 mm²/s (AUC = 0.85, p < 0.001, sensitivity/specificity/accuracy 79%/93%/86% in per LN-analysis and 94%/86%/91% in per-patient analysis). The optimal cut-off for ADC_ratio was 1.15 (AUC = 0.80, p < 0.001, sensitivity/specificity/accuracy 69%/93%/81% and 76%,93%/84%). Excellent inter- and intra-operators’ agreements were observed.
In patients with CLM, ADC values < 1.48 x 10^-3 mm²/s can be postulated as a cut-off to distinguish metastatic LNs.
Is Cure Possible After Sequential Resection of Hepatic and Pulmonary Metastases From Colorectal Cancer?
2018, Clinical Colorectal Cancer
Surgical resection is an established therapeutic strategy for colorectal cancer (CRC) metastasis. However, controversies exist when CRC liver and lung metastases (CLLMs) are found concomitantly or when recurrence develops after either liver or lung resection. No predictive score model is available to risk stratify these patients in preparation for surgery, and cure has not yet been reported.
All consecutive patients who had undergone surgery for CLLMs at our institution during a 20-year period were reviewed. Our policy was to propose sequential surgery of both sites with perioperative chemotherapy, if the strategy was potentially curative. Overall survival, disease-free survival, and cure were evaluated.
Sequential resection was performed in 150 patients with CLLMs. The median number of liver and lung metastases resected was 3 and 1, respectively. The median follow-up period was 59 months (range, 7-274 months). The median, 5-year, and 10-year overall survival was 76 months, 60%, and 35% respectively. CRC that was metastatic at the initial diagnosis (P = .012), a prelung resection carcinoembryonic antigen level > 100 ng/mL (P = .014), a prelung resection cancer antigen 19-9 level > 37 U/mL (P = .034), and an interval between liver and lung resection of < 24 months (P = .024) were independent poor prognostic factors for survival. The 5-year survival was significantly different for patients with ≤ 2 and ≥ 3 risk factors (77.3% vs. 26.5%). Of 75 patients with ≥ 5 years of follow-up data available from the first metastasis resection, 15 (20%) with disease-free survival ≥ 5 years were considered cured. The use of targeted therapy was the only independent predictor of cure.
Curative-intent surgery provides good long-term survival and offers a chance of cure in select patients. Patients with ≤ 2 risk factors are good candidates for sequential resection.
Surgical treatment options following chemotherapy plus cetuximab or bevacizumab in metastatic colorectal cancer—central evaluation of FIRE-3
2018, European Journal of Cancer
The FIRE-3 trial investigated combination chemotherapy plus either cetuximab or bevacizumab in patients with untreated metastatic colorectal cancer (mCRC) not scheduled for upfront surgery. We aimed to determine the number of patients who present with potentially resectable disease during systemic first-line therapy and to compare the findings with study reports concerning resections and outcome.
This evaluation of 448 patients was performed as central review blinded for treatment, other reviewers' evaluations and conducted interventions. Resectability was defined if at least 50% of the reviewers recommended surgical-based intervention. Overall survival was assessed by Kaplan–Meier method.
Resectability increased from 22% (97/448) at baseline before treatment to 53% (238/448) at best response (P < 0.001), compared with an actual secondary resection rate for metastases of 16% (72/448). At baseline (23% versus 20%) and best response (53% versus 53%), potential resectability of metastases in this molecular unselected population was similar in cetuximab-treated patients versus bevacizumab-treated patients and not limited to patients with one-organ disease. The actual resection rate of metastases was significantly associated with treatment setting (P = 0.02; university hospital versus hospital/practice). Overall survival was 51.3 months (95% confidence interval [CI] 35.9–66.7) in patients with resectable disease who received surgery, 30.8 months (95% CI 26.6–34.9) in patients with resectable disease without surgery and 18.6 months (95% CI 15.8–21.3) in patients with unresectable disease (P < 0.001).
Our findings illustrate the potential for conversion to resectability in mCRC, certain reluctance towards metastatic resections in clinical practice and the need for pre-planned and continuous evaluation for metastatic resection in high-volume centres.
NCT00433927.

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ReviewLiver resection for metastatic colorectal cancer in the presence of extrahepatic disease

Summary

Introduction

Section snippets

Portal lymph-node metastases

Pulmonary metastases

Peritoneal metastases

Studies of combined sites of extrahepatic disease

Conclusion

Search strategy and selection criteria

Curr Probl Surg

Ann Oncol

J Am Coll Surg

Clin Colorectal Cancer

J Am Coll Surg

J Thorac Cardiovasc Surg

J Am Coll Surg

J Am Coll Surg

J Am Coll Surg

Ann Thorac Surg

Eur J Surg Oncol

Eur J Surg Oncol

Surgery

Actual 10-year survival after resection of colorectal liver metastases defines cure

J Clin Oncol

Resection of hepatic metastases from colorectal cancer

Arch Surg

Determinants of survival in liver resection for colorectal secondaries

Br J Surg

Resection of the liver for colorectal carcinoma metastases: a multi-institutional study of patterns of recurrence

Surgery

Biweekly chemotherapy with oxaliplatin, irinotecan, infusional fluorouracil, and leucovorin: a pilot study in patients with metastatic colorectal cancer

J Clin Oncol

Concurrent irinotecan, oxaliplatin and UFT in first-line treatment of metastatic colorectal cancer: a phase I study

Br J Cancer

Lymphatic dissemination of hepatic metastases. Implications for the follow-up and treatment of patients with colorectal cancer

Cancer

Significance of lymph node involvement at the hepatic hilum in the resection of colorectal liver metastases

Br J Surg

Perioperative blood transfusion and determinants of survival after liver resection for metastatic colorectal carcinoma

Ann Surg

Hepatic lymph node involvement in resected cases of liver metastases from colorectal cancer

Dis Colon Rectum

Prospective study of microscopic lymph node involvement of the hepatic pedicle during curative hepatectomy for colorectal metastases

Br J Surg

The role of lymphadenectomy for liver tumors: further considerations on the appropriateness of treatment strategy

Ann Surg

Review
Liver resection for metastatic colorectal cancer in the presence of extrahepatic disease