Systemic cytotoxic and biological therapies of colorectal liver metastases: expert consensus statement

Systemic therapy for colorectal cancer liver metastases (CRLM) has undergone significant development in the past 15 years. Therapy regimens consisting of combinations of cytotoxic chemotherapeutic agents have demonstrated greater efficacy and contributed to a significant survival improvement. As the majority of patients who undergo resection for liver-only CRLM are at risk of disease recurrence and cancer-related death, combining resection with systemic therapy appears sensible. However, trial-based evidence is sparse to support this concept. Peri-operative FOLFOX has demonstrated a progression-free survival benefit in a single Phase III trial; the safety of chemotherapy and subsequent operations was acceptable and only a few patients showed initial progression. Chemotherapy-associated liver injury (CALI), including sinusoidal obstruction syndrome and steatohepatitis, has been observed after cytotoxic therapy, and should have implications for chemotherapy plans prior to hepatectomy. In general, pre-operative chemotherapy should not extend beyond 3 months. For patients with unresectable liver-only CRLM, a response to chemotherapy could establish resectability and should be considered an initial treatment goal. In patients with unresectable CRLM, oxaliplatin- or irinotecan-containing combinations represent the standard options, although single-agent choices may be appropriate for individual patients. The addition of bevacizumab carries the potential for a greater response and possibly for reduced CALI risks. In tumours without K-ras mutations, anti-epidermal growth factor receptor (EGFR) agents are also reasonable choices for a greater response and improved survival outcomes. It is crucial that all systemic CRLM treatment decisions include proper definitions of treatment goals and endpoints, and are derived based on appropriate multidisciplinary considerations for other potentially applicable local or regional modalities.     

Locoregional surgical and interventional therapies for advanced colorectal cancer liver metastases: expert consensus statements

Selection of the optimal surgical and interventional therapies for advanced colorectal cancer liver metastases (CRLM) requires multidisciplinary discussion of treatment strategies early in the trajectory of the individual patient''s care. This paper reports on expert consensus on locoregional and interventional therapies for the treatment of advanced CRLM. Resection remains the reference treatment for patients with bilateral CRLM and synchronous presentation of primary and metastatic cancer. Patients with oligonodular bilateral CRLM may be candidates for one-stage multiple segmentectomies; two-stage resection with or without portal vein embolization may allow complete resection in patients with more advanced disease. After downsizing with preoperative systemic and/or regional therapy, curative-intent hepatectomy requires resection of all initial and currently known sites of disease; debulking procedures are not recommended. Many patients with synchronous primary disease and CRLM can safely undergo simultaneous resection of all disease. Staged resections should be considered for patients in whom the volume of the future liver remnant is anticipated to be marginal or inadequate, who have significant medical comorbid condition(s), or in whom extensive resections are required for the primary cancer and/or CRLM. Priority for liver-first or primary-first resection should depend on primary tumour-related symptoms or concern for the progression of marginally resectable CRLM during treatment of the primary disease. Chemotherapy delivered by hepatic arterial infusion represents a valid option in patients with liver-only disease, although it is best delivered in experienced centres. Ablation strategies are not recommended as first-line treatments for resectable CRLM alone or in combination with resection because of high local failure rates and limitations related to tumour size, multiplicity and intrahepatic location.     

Perioperative chemotherapy and liver resection for hepatic metastases of colorectal cancer

Surgical resection has played a major role in the treatment for colorectal liver metastases. The safety and efficacy of surgery for liver metastasis are obvious, although there are some differences between the western countries and Japan concerning the surgical indication, procedures, timing of chemotherapies in a perioperative period, and treatment of a primary disease. In future, long-term outcomes after surgical resection for colorectal liver metastases would be expected to be prolonged by combination of surgery and chemotherapies.     

Repeat hepatic resection in patients with colorectal liver metastases

AIM:To investigate the survival outcomes of secondaryhepatectomy for recurrent colorectal liver metastases(CRLM).METHODS:From October 1994 to December 2009,patients with CRLM who underwent surgical treatment with curative intent were investigated.Patients were divided into two groups:patients who underwent primary hepatectomy(Group 1)and those who underwent secondary hepatectomy for recurrent CRLM(Group 2).RESULTS:Survival and prognostic factors were analyzed.A total of 461 patients were included:406patients in Group 1 and 55 patients in Group 2.After a median 39-mo(range,3-195 mo)follow-up,there was a significant difference between Groups 1 and 2in terms of disease-free survival(P=0.029)although there was no significant difference in overall survival(P=0.206).Secondary hepatectomy was less effective in patients with multiple recurrent CRLM than primary hepatectomy for initial CRLM(P=0.008).Multiple CRLM and radiofrequency ablation therapy were poor prognostic factors of secondary hepatectomy in multivariate Cox regression analysis(P=0.006,P=0.004,respectively).CONCLUSION:Secondary hepatectomy for single recurrent CRLM is as effective as primary surgical treatment for single recurrent CRLM.However,secondary hepatectomy for multiple recurrent CRLM is less effective than that for single recurrent CRLM.     

Prognostic factors following liver resection for hepatic metastases from colorectal cancer

AIM: To determine the impact of prognostic factors on survival of patients with metastases from colorectal cancer that underwent liver resection. METHODS: The records of 28 patients that underwent liver resection for metastases from colorectal cancer between April 1992 and September 2001 were retrospectively analyzed. Thirty-eight resections were performed (more than one resection in eight patients and two patients underwent re-resections). The primary tumor was resected in all the patients. A screening protocol for liver metastases including clinical examinations every three months, ultrassonography and CEA level until 5 years of follow-up and after every 6 months, was applied. The prognostic factors analyzed regarding the impact on survival were: Dukes C stage of primary tumor, size of metastasis >5 cm, a disease-free interval from primary tumor to metastasis < 1 year, CEA level > 100 ng/mL, resection margins < 1 cm and extrahepatic disease. The Kaplan-Meier curves, log rank and Cox regression were used for the statistical analysis. RESULTS: Perioperative morbidity and mortality were 39.3% and 3.6%, respectively. The 5-year survival rate was 35%. The independent prognostic factors were: disease-free interval from primary tumor to metastasis < 1 year and extrahepatic disease. CONCLUSIONS: The liver resection for metastases from colorectal cancer is a safe procedure with more than 30% 5-year survival. Disease-free interval from primary tumor to metastasis < 1 year and extrahepatic disease were independent prognostic factors.     

Prognostic factors following liver resection for hepatic metastases from colorectal cancer

BACKGROUND/AIMS: We aimed to identify prognostic factors that may allow better patient selection for liver resection for colorectal liver metastases. METHODOLOGY: A retrospective analysis of the files of 120 patients undergoing liver resection for colorectal metastases between 9/85 and 12/96 was performed. Survival and disease-free survival were calculated, and a uni- and multivariate analysis for the prognostic impact of various perioperative factors on survival was performed. RESULTS: Perioperative morbidity and mortality were 28.3% and 5.8% respectively. Median overall survival was 30 months with a 5-year survival rate of 31%. Radicality was the prime prognostic determinant. In patients with R0-resection, a liver metastasis of > 3.5 cm in diameter was the only independent factor associated with an adverse prognosis. CONCLUSIONS: Liver resection for colorectal liver metastases should be attempted if complete resection with clear margins is feasible and may be especially beneficial in patients with small (< or = 3.5 cm) lesions.     

Aggressive liver resection including major-vessel resection for colorectal liver metastases

AIM: To clarify short- and long-term outcomes of combined resection of liver with major vessels in treating colorectal liver metastases.METHODS: Clinicopathologic data were evaluated for 312 patients who underwent 371 liver resections for metastases from colorectal cancer. Twenty-five patients who underwent resection and reconstruction of retrohepatic vena cava, major hepatic veins, or hepatic venous confluence during hepatectomies were compared with other patients, who underwent conventional liver resections.RESULTS: Morbidity was 20% (75/371) and mortality was 0.3% (1/312) in all patients after hepatectomy. Hepatic resection combined with major-vessel resection/reconstruction could be performed with acceptable morbidity (16%) and no mortality. By multivariate analysis, repeat liver resection (relative risk or RR, 5.690; P = 0.0008) was independently associated with resection/reconstruction of major vessels during hepatectomy, as were tumor size exceeding 30 mm (RR, 3.338; P = 0.0292) and prehepatectomy chemotherapy (RR, 3.485; P = 0.0083). When 312 patients who underwent a first liver resection for initial liver metastases were divided into those with conventional resection (n = 296) and those with combined resection of liver and major vessels (n = 16), overall survival and disease-free rates were significantly poorer in the combined resection group than in the conventional resection group (P = 0.02 and P < 0.01, respectively). A similar tendency concerning overall survival was observed for conventional resection (n = 37) vs major-vessel resection combined with liver resection (n = 7) performed as a second resection following liver recurrences (P = 0.09). Combined major-vessel resection at first hepatectomy (not performed; 0.512; P = 0.0394) and histologic major-vessel invasion at a second hepatectomy (negative; 0.057; P = 0.0005) were identified as independent factors affecting survival by multivariate analysis.CONCLUSION: Hepatic resection including major-vessel resection/reconstruction for colorectal liver metastases can be performed with acceptable operative risk. However, such aggressive approaches are beneficial mainly in patients responding to effective prehepatectomy chemotherapy.     

Laparoscopic resection of hepatic colorectal metastases

BackgroundLiver resection for secondary malignancy has become the standard of care in appropriately staged patients, offering 5-year survival rates of >40%. Reports of laparoscopic liver resection have been published with increasing frequency over the last few years. In these small series approximately one-third of all operations have been for malignancy, but survival figures cannot be assessed yet.MethodsA retrospective review of all laparoscopic liver resections performed by four surgeons in Brisbane between 1997 and 2004 was done. Follow-up was by regular patient review and telephone confirmation.ResultsOf 84 laparoscopic liver resections, 33 (39%) were for malignancy; 28 of these were for metastases (22 colorectal). Thirteen patients had left lateral sectionectomy with minimal morbidity; nine right hepatectomies were attempted and six cases of segmental or subsegmental resection were performed. Survival rates in 12 patients followed for 2 years with colorectal secondaries were 75% with 67% disease-free.DiscussionLaparoscopic liver resection is feasible in highly selected cases of malignant disease. Patients need to be appropriately staged and surgeons need a broad experience of open liver surgery and advanced laparoscopic procedures.     

Hilar Cholangiocarcinoma: expert consensus statement

An American Hepato-Pancreato-Biliary Association (AHPBA)-sponsored consensus meeting of expert panellists met on 15 January 2014 to review current evidence on the management of hilar cholangiocarcinoma in order to establish practice guidelines and to agree consensus statements. It was established that the treatment of patients with hilar cholangiocarcinoma requires a coordinated, multidisciplinary approach to optimize the chances for both durable survival and effective palliation. An adequate diagnostic and staging work-up includes high-quality cross-sectional imaging; however, pathologic confirmation is not required prior to resection or initiation of a liver transplant trimodal treatment protocol. The ideal treatment for suitable patients with resectable hilar malignancy is resection of the intra- and extrahepatic bile ducts, as well as resection of the involved ipsilateral liver. Preoperative biliary drainage is best achieved with percutaneous transhepatic approaches and may be indicated for patients with cholangitis, malnutrition or hepatic insufficiency. Portal vein embolization is a safe and effective strategy for increasing the future liver remnant (FLR) and is particularly useful for patients with an FLR of <30%. Selected patients with unresectable hilar cholangiocarcinoma should be evaluated for a standard trimodal protocol incorporating external beam and endoluminal radiation therapy, systemic chemotherapy and liver transplantation. Post-resection chemoradiation should be offered to patients who show high-risk features on surgical pathology. Chemoradiation is also recommended for patients with locally advanced, unresectable hilar cancers. For patients with locally recurrent or metastatic hilar cholangiocarcinoma, first-line chemotherapy with gemcitabine and cisplatin is recommended based on multiple Phase II trials and a large randomized controlled trial including a heterogeneous population of patients with biliary cancers.     

Gallbladder Cancer: expert consensus statement

An American Hepato-Pancreato-Biliary Association (AHPBA)-sponsored consensus meeting of expert panellists was convened on 15 January 2014 to review current evidence on the management of gallbladder carcinoma in order to establish practice guidelines. In summary, within high incidence areas, the assessment of routine gallbladder specimens should include the microscopic evaluation of a minimum of three sections and the cystic duct margin; specimens with dysplasia or proven cancer should be extensively sampled. Provided the patient is medically fit for surgery, data support the resection of all gallbladder polyps of >1.0 cm in diameter and those with imaging evidence of vascular stalks. The minimum staging evaluation of patients with suspected or proven gallbladder cancer includes contrasted cross-sectional imaging and diagnostic laparoscopy. Adequate lymphadenectomy includes assessment of any suspicious regional nodes, evaluation of the aortocaval nodal basin, and a goal recovery of at least six nodes. Patients with confirmed metastases to N2 nodal stations do not benefit from radical resection and should receive systemic and/or palliative treatments. Primary resection of patients with early T-stage (T1b–2) disease should include en bloc resection of adjacent liver parenchyma. Patients with T1b, T2 or T3 disease that is incidentally identified in a cholecystectomy specimen should undergo re-resection unless this is contraindicated by advanced disease or poor performance status. Re-resection should include complete portal lymphadenectomy and bile duct resection only when needed to achieve a negative margin (R0) resection. Patients with preoperatively staged T3 or T4 N1 disease should be considered for clinical trials of neoadjuvant chemotherapy. Following R0 resection of T2–4 disease in N1 gallbladder cancer, patients should be considered for adjuvant systemic chemotherapy and/or chemoradiotherapy.     

Intrahepatic Cholangiocarcinoma: expert consensus statement

An American Hepato-Pancreato-Biliary Association (AHPBA)-sponsored consensus meeting of expert panellists met on 15 January 2014 to review current evidence on the management of intrahepatic cholangiocarcinoma (ICC) in order to establish practice guidelines and to agree on consensus statements. The treatment of ICC requires a coordinated, multidisciplinary approach to optimize survival. Biopsy is not necessary if the surgeon suspects ICC and is planning curative resection, although biopsy should be obtained before systemic or locoregional therapies are initiated. Assessment of resectability is best accomplished using cross-sectional imaging [computed tomography (CT) or magnetic resonance imaging (MRI)], but the role of positron emission tomography (PET) is unclear. Resectability in ICC is defined by the ability to completely remove the disease while leaving an adequate liver remnant. Extrahepatic disease, multiple bilobar or multicentric tumours, and lymph node metastases beyond the primary echelon are contraindications to resection. Regional lymphadenectomy should be considered a standard part of surgical therapy. In patients with high-risk features, the routine use of diagnostic laparoscopy is recommended. The preoperative diagnosis of combined hepatocellular carcinoma and cholangiocarcinoma (cHCC–CC) by imaging studies is extremely difficult. Surgical resection remains the mainstay of treatment, but survival is worse than in HCC alone. There are no adequately powered, randomized Phase III trials that can provide definitive recommendations for adjuvant therapy for ICC. Patients with high-risk features (lymphovascular invasion, multicentricity or satellitosis, large tumours) should be encouraged to enrol in clinical trials and to consider adjuvant therapy. Cisplatin plus gemcitabine represents the standard-of-care, front-line systemic therapy for metastatic ICC. Genomic analyses of biliary cancers support the development of targeted therapeutic interventions.     

Influence of resection margin on survival in hepatic resections for colorectal liver metastases

Background:

Traditionally a 1-cm margin has been accepted as the gold standard for resection of colorectal liver metastases. Evidence is emerging that a lesser margin may provide equally acceptable outcomes, but a critical margin, below which recurrence is higher and survival poorer, has not been universally agreed. In a recent publication, we reported peri-operative morbidity and clear margin as the two independent prognostic factors. The aim of the current study was to further analyse the effect of the width of the surgical margin on patient survival to determine whether a margin of 1 mm is adequate.

Methods:

Two hundred and sixty-one consecutive primary liver resections for colorectal metastases were analysed from 1992 to 2007. The resection margins were assessed by microscopic examination of paraffin sections. The initial analysis was performed on five groups according to the resection margins: involved margin, 0–1 mm, >1–<4 mm, 4–<10 mm and ≥ 10 mm. Subsequent analysis was based on two groups: margin <1 mm and >1 mm.

Results:

With a median follow-up of 4.7 years, the overall 5-year patient and disease-free survival were 38% and 22%, respectively. There was no significant difference in patient- or disease-free survival between the three groups with resection margins >1 mm. When a comparison was made between patients with resection margins ≤1 mm and patients with resection margins >1 mm, there was a significant 5-year patient survival difference of 25% versus 43% (P < 0.04). However, the disease-free survival difference did not reach statistical significance (P= 0.14).

Conclusions:

In this cohort of patients, we have demonstrated that a resection margin of greater than 1 mm is associated with significantly improved 5-year overall survival, compared with involved margins or margins less than or equal to 1 mm. The possible beneficial effect of greater margins beyond 1 mm could not be demonstrated.     

Limiting factors for liver regeneration after a major hepatic resection for colorectal cancer metastases

Background

Chemotherapy before resection of colorectal metastases in the liver is extensively used and has been shown to induce histopathological changes in the liver parenchyma, although little is known about the effect of chemotherapy on liver regeneration. The aim of this study was to determine if pre-operative chemotherapy influences the regenerated liver volume after a major liver resection.

Patients and methods

This retrospective cohort study included 74 patients subjected to a major liver resection for colorectal metastases. Patients were divided into two groups depending on whether they had been treated with chemotherapy less than 3 months before surgery or not. Liver volumes were measured before and 1 year after resection.

Results

Pre-operative chemotherapy reduced volumetric liver regeneration (83 ± 2% versus 91 ± 2%; P = 0.007) as compared with patients without chemotherapy. There was a linear correlation between regenerated volume and time interval between the end of chemotherapy to resection (P = 0.031).

Conclusions

Pre-operative chemotherapy in patients with colorectal liver metastases negatively affects volume regeneration after a partial hepatectomy. The time interval between chemotherapy and surgery determines the impact of these affects.     

The argument for liver resection in colorectal liver metastases

The first liver resection for colorectal metastasis was performed by Cattell in 1940. Unfortunately, there has never been a randomized control trial for liver resection against other treatment modalities (best supportive care, palliative chemotherapy, etc). Since this operation is now well established in the surgical repertoire, it would now be ethically difficult to undertake such a trial.