A randomized two arm phase III study in patients post radical resection of liver metastases of colorectal cancer to investigate bevacizumab in combination with capecitabine plus oxaliplatin (CAPOX) vs CAPOX alone as adjuvant treatment

Background  

About 50% of patients with colorectal cancer are destined to develop hepatic metastases. Radical resection is the most effective treatment for patients with colorectal liver metastases offering five year survival rates between 36-60%. Unfortunately only 20% of patients are resectable at time of presentation. Radiofrequency ablation is an alternative treatment option for irresectable colorectal liver metastases with reported 5 year survival rates of 18-30%. Most patients will develop local or distant recurrences after surgery, possibly due to the outgrowth of micrometastases present at the time of liver surgery. This study aims to achieve an improved disease free survival for patients after resection or resection combined with RFA of colorectal liver metastases by adding the angiogenesis inhibitor bevacizumab to an adjuvant regimen of CAPOX.     

Microwave ablation with or without resection for colorectal liver metastases

Background

Ablation with or without resection for colorectal liver metastases has been suggested as a potential method of improving survival if complete surgical resection is not possible. This study assessed the safety and efficacy of surgical microwave ablation (MWA) with or without resection for colorectal liver metastases.

Methods

A retrospective case series was reviewed. Data was extracted for all patients treated with open MWA with or without resection for colorectal liver metastases. Endpoints included postoperative 30-day morbidity and mortality, local treatment failure, disease free survival and overall survival.

Results

A total of 43 patients with technically irresectable disease were treated with MWA; 28 underwent combined MWA and resection, whilst 15 underwent MWA as the sole treatment modality. Overall post-operative morbidity was 35%, 30-day postoperative mortality 2%. At a median follow-up of 15 months, local treatment failure was observed in 4% of ablated lesions. 3-year OS was 36% for MWA group, compared to 45% for the combined ablate/resect group with 3-year DFS of 32% and 8% respectively.

Conclusion

Microwave ablation with or without resection is a safe and effective method of achieving local disease control. Ablation with or without resection is associated with good long-term outcomes, and may be a suitable treatment option for small non-resectable colorectal liver metastases.     

Importance of response to neoadjuvant chemotherapy in potentially curable colorectal cancer liver metastases

Background  

Surgical resection of liver metastases arising from colorectal cancer is considered the only curative treatment option. However, many patients subsequently experience disease recurrence. We prospectively investigated whether neoadjuvant chemotherapy reduces the risk of recurrence following potentially curative liver resection. Special emphasis was directed to the importance of response.     

Métastases hépatiques des cancers colorectaux : intérêt du traitement d’induction dans l’optimisation des résections. À propos de neuf cas

Introduction

A multidisciplinary approach and advance in surgery and chemotherapy has been made to increase the number of patients who could be candidates for surgical resection. We try to assess the value of this treatment in strategies to treat primary unresectable liver metastases.

Materials and methods

From January 2005 to December 2008, we treated nine patients with primary unresectable liver metastases from colorectal cancer.

Results

There were 32 cases of liver metastases from colorectal carcinoma, 9 of them were primary unresectable liver metastases. After chemotherapy, radiofrequency and portal vein ligation, these metastases became eligible for curative resection: neoadjuvant chemotherapy (3 cases), chemotherapy + radiofrequency (3 cases), chemotherapy + portal vein ligation + two-stage hepatectomy (2 cases), chemotherapy + portal vein ligation (1 case). There were no surgical deaths. The postoperative death rate was 22.2% (15, 20 months).

Conclusion

To date, surgical resection remains the only treatment that can ensure long-term survival and cure in some patients; allowing treatment, with curative intent, of metastases initially considered as unresectable.     

Colorectal Liver Metastases with Extrahepatic Disease—A New Criteria for Oncologic Resection?

Background  

Emerging data suggest that in the current era of modern systemic therapies, resection of colorectal liver metastases with concomitant extrahepatic disease may be a curative option in selected patients.     

Survival after lung metastasectomy for colorectal cancer: Importance of previous liver metastasis as a prognostic factor

Aims

To analyse patient survival after the resection of lung metastases from colorectal carcinoma and specifically to verify whether presence of liver metastasis prior to lung metastasectomy affects survival.

Methods

All patients who, between 1998 and 2008, underwent lung metastasectomy due to colorectal cancer were included in the study. Kaplan-Meier survival analysis was performed with the log-rank test and Cox regression multivariate analysis.

Results

During this period, 101 metastasectomies were performed on 84 patients. The median age of patients was 65.4 years, and 60% of patients were male. The 30-day mortality rate was 2%, and incidence of complications was 7%. The overall survival was 72 months, with 3-and 5-year survival rates of 70% and 54%, respectively. A total of 17 patients (20%) had previously undergone resection of liver metastasis. No significant differences were found in the distribution of what were supposed to be the main variables between patients with and without previous hepatic metastases. Multivariate analysis identified the following statistically significant factors affecting survival: previous liver metastasectomy (p = 0.03), tumour-infiltrated pulmonary lymph nodes (p = 0.04), disease-free interval ≥ 48 months (p = 0.03), and presence of more than one lung metastasis (p < 0.01). In patients with previous liver metastasis, the shorter the time between primary colorectal surgery and the hepatectomy, the lower the survival rate after pulmonary metastasectomy (p = 0.048).

Conclusions

A previous history of liver metastasis shortens survival after lung metastasectomy. The time between hepatic resection and lung metastasectomy does not affect survival; however, patients with synchronous liver metastasis and colorectal neoplasia have poorer survival rates than those with metachronous disease.     

A phase II experience with neoadjuvant irinotecan (CPT-11), 5-fluorouracil (5-FU) and leucovorin (LV) for colorectal liver metastases

Background  

Chemotherapy may improve survival in patients undergoing resection of colorectal liver metastases (CLM). Neoadjuvant chemotherapy may help identify patients with occult extrahepatic disease (averting unnecessary metastasectomy), and it provides in vivo chemosensitivity data.     

Gadoxetic acid-enhanced 3.0 T MR imaging versus multidetector-row CT in the detection of colorectal metastases in fatty liver using intraoperative ultrasound and histopathology as a standard of reference

Objective

To compare the diagnostic value of gadoxetic acid-enhanced MRI at 3.0 T with 64-row MDCT in the detection of colorectal liver metastases in diffuse fatty infiltration of the liver after neoadjuvant chemotherapy.

Methods

Twenty-three patients with colorectal liver metastases and at moderate to severe steatosis (25–90%) underwent prospectively preoperative tri-phasic MDCT (Somatom Sensation 64, Siemens) and gadoxetic acid-enhanced MRI (3-T Magnetom Trio, Siemens). All patients underwent surgical resection of liver metastases. Intraoperative ultrasound (IOUS) was carried out, which served as the standard of reference, together with histopathology.

Results

Overall, 68 metastases (range, 0.4–6 cm; 31/68 metastases [46%] ≤ 1 cm) were found at histology. MDCT detected 49/68 lesions (72%), and MRI 66/68 (97%, p < 0.001). For lesions ≤1 cm, MDCT detected only 13/31 (41.9%) and MRI 29/31 (93%, p < 0.001). Eight false-positive lesions were detected by MDCT, seven small lesions by MRI. There was no statistically significant difference between the two modalities in the detection of lesions >1 cm (p = 0.250). IOUS detected all metastases and revealed two false-positive diagnoses.

Conclusion

Gadoxetic acid-enhanced 3.0 T MRI is superior to 64-row MDCT in detecting colorectal liver metastases ≤1 cm during preoperative staging in patients with liver steatosis. A combination of MRI and IOUS may further improve the outcome of surgical treatment.     

R1 resection for aggressive or advanced colorectal liver metastases is justified in combination with effective prehepatectomy chemotherapy

Aims

Here we reassess anticipated inability to obtain a microscopically clear surgical margin as an absolute contraindication to surgery for colorectal liver metastases in view of improvements in treatment modalities adjunctive to surgery.

Methods

We retrospectively analysed 310 patients treated at our institution to estimate the survival benefit from R1 hepatectomy performed to remove liver metastases from colorectal cancer.

Results

Considering all 310 patients evaluated, the R1 resection group (positive margin; n = 55) showed a lower disease-free rate (P < 0.01) and worse overall survival (P < 0.01) than the R0 resection group (negative margin; n = 255). When patients were divided according to initial resectability, similar differences in disease-free rate and overall survival (P = 0.03) between R1 (n = 19) and R0 (n = 182) were observed in patients whose metastases were resectable. However, superior impact of R0 resection (n = 73) compared to R1 resection (n = 36) on disease-free rate (P = 0.44) and overall survival (P = 0.50) was not confirmed in patients with initially unresectable or marginally resectable metastases, especially those with a favourable response to prehepatectomy chemotherapy.

Conclusions

A predicted positive surgical margin after resection no longer should be an absolute contraindication to surgery for aggressive or advanced liver metastases.     

Pulmonary resection of colorectal metastases in patients with or without a history of hepatic metastases

Introduction

In selected patients with isolated colorectal lung or liver metastases resection can provide an increase in overall survival and even cure. Here, we evaluate whether also patients with combined or sequential metastatic disease to liver and lung may still be candidates for surgical resection.

Methods

From 1997 till 2006 39 patients underwent pulmonary metastasectomy. Two subgroups were identified: resection of pulmonary metastases only (PM) and resection of hepatic and later pulmonary metastases (LPM).

Results

Patient characteristics were identical in both groups. Median follow-up in group PM was 35 months and 38 months in group LPM. Two-year survival in group PM was 61%, and in group LPM 81% (p = NS). Five-year survival was 30% and 20% in PM and LPM groups, respectively (p = NS). The median disease free survival was 12 months in the PM group and 13 months in the LPM group.The extent of pulmonary resection had no impact on survival. Complications occurred in seven patients in the PM group and two patients in the LPM group. Complication rate and severity were related to the extent of pulmonary resection. A small group of patients underwent repeated pulmonary resection without serious complications.

Conclusion

Resection of pulmonary colorectal metastases may improve survival, even in patients who underwent hepatic resection for colorectal liver metastases at an earlier stage.     

Resectable Colorectal Liver Metastases: Optimal Sequencing of Chemotherapy

Background  

Hepatic resection is a potentially curative option for patients with colorectal liver metastases who are candidates for surgery. With the increasing availability of highly effective chemotherapy, surgery may be further advanced by the improved tumor response and better long-term outcomes associated with its use in the perioperative setting.     

ELR+ CXC chemokine expression in benign and malignant colorectal conditions

Background  

CXCR2 chemokine ligands CXCL1, CXCL5 and CXCL6 were shown to be involved in chemoattraction, inflammatory responses, tumor growth and angiogenesis. Here, we comparatively analyzed their expression profile in resection specimens from patients with colorectal adenoma (CRA) (n = 30) as well as colorectal carcinoma (CRC) (n = 48) and corresponding colorectal liver metastases (CRLM) (n = 16).     

Liver resection for metastatic colorectal leiomyosarcoma: a single center experience

Background

Leiomyosarcoma arising in the colorectum is a rare malignancy of the smooth muscles accounting for less than 1% of gastrointestinal tumors. Surgery remains the most accepted modality for the treatment of this entity however management of liver metastases remains controversial.

Methods & results

From 1998 to 2009, five patients diagnosed with primary leiomyosarcoma of colorectal origin with metastatic liver disease, underwent liver resections at the American University of Beirut Medical Center. The median overall survival was 47 months (range, 7-135 months).

Conclusions

Leiomyosarcoma of colorectal origin with liver metastasis is a very rare entity. Long-term survival can be achieved after surgical resection and should be considered for all patients.     

Surgeon's awareness of the synchronous liver metastases during colorectal cancer resection may affect outcome

Aim

There is conflicting evidence about the importance of synchronous metastases upon tumor outcome. The aim of this study is to identify the effect of finding synchronous colorectal liver metastases on the performance of the surgeon whilst operating on primary colorectal cancer.

Methods

Patients with completed colorectal cancer data who underwent liver resection for colorectal metastases between 1993 and 2001 were included. Two hundred seventy patients were categorised according to the site of the primary tumour (colon or rectum) and knowledge of the presence of liver metastases by the colorectal surgeon (SA = surgeon aware, n = 112, SNA = surgeon not aware, n = 158). The number of retrieved lymph nodes and colorectal resection margin involvement were used as surgical performance indicators. Survival and local recurrence rate were monitored.

Results

The SA group had a higher rate of colorectal circumferential resection margin involvement, the local and intra-abdominal recurrence rate was also significantly higher in this group (p < 0.001).

Conclusions

Awareness of the presence of liver metastases by the operating surgeon is an independent predictor of intra abdominal extra hepatic recurrence of colorectal cancer following potentially curative hepatic resection. This is related to an increased rate of primary colorectal resection margin involvement.     

Bevacizumab improves survival in patients with synchronous colorectal liver metastases provided the primary tumor is resected first

Background

Multimodal strategy including chemotherapy and hepatectomy is advocated for the management of colorectal liver metastases (CRLM). The aim of this study was to evaluate the impact of neoadjuvant Bevacizumab-based chemotherapy on survival in patients with resected stage IVA colorectal cancer and liver metastases.

Methods

Data from 120 consecutive patients who received neoadjuvant chemotherapy and underwent curative-intent hepatectomy for synchronous CRLM were retrospectively reviewed. Overall survival (OS) was stratified according to administration of Bevacizumab before liver resection and surgical strategy, i.e., classical strategy (primary tumor resection first) versus reverse strategy (liver metastases resection first).

Results

Patients who received Bevacizumab (n?=?37; 30%) had a higher number of CRLM (p?=?0.003) and underwent more often reverse strategy (p?=?0.005), as compared to those who did not (n?=?83; 70%). Bevacizumab was associated with an improved OS compared with conventional chemotherapy (p?=?0.04). After stratifying by the surgical strategy, Bevacizumab was associated with improved OS in patients who had classical strategy (p?=?0.03). In contrast, Bevacizumab had no impact on OS among patients who had liver metastases resection first (p?=?0.89).

Conclusions

Neoadjuvant Bevacizumab-based chemotherapy was associated with improved OS in patients who underwent liver resection of synchronous CRLM, especially in those who underwent primary tumor resection first.

     

Two-stage hepatectomy: Who will not jump over the second hurdle?

Background

Two-stage hepatectomy uses compensatory liver regeneration after a first noncurative hepatectomy to enable a second curative resection in patients with bilobar colorectal liver metastasis (CLM).

Objective

To determine the predictive factors of failure of two-stage hepatectomy.

Method

Between 2000 and 2010, 48 patients with irresecable CLM were eligible for two-stage hepatectomy. The planned strategy was a) cleaning of the left hepatic lobe (first hepatectomy), b) right portal vein embolisation and c) right hepatectomy (second hepatectomy). Six patients had occult CLM (n = 5) or extra-hepatic disease (n = 1), which was discovered during the first hepatectomy. Thus, 42 patients completed the first hepatectomy and underwent portal vein embolisation in order to receive the second hepatectomy. Eight patients did not undergo a second hepatectomy due to disease progression.

Results

Upon univariate analysis, two factors were identified that precluded patients from having the second hepatectomy: the combined resection of a primary tumour during the first hepatectomy (p = 0.01) and administration of chemotherapy between the two hepatectomies (p = 0.03). An independent association with impairment to perform the two-stage strategy was demonstrated by multivariate analysis for only the combined resection of the primary colorectal cancer during the first hepatectomy (p = 0.04).

Conclusion

Due to the small number of patients and the absence of equivalent conclusions in other studies, we cannot recommend performance of an isolated colorectal resection prior to chemotherapy. However, resection of an asymptomatic primary tumour before chemotherapy should not be considered as an outdated procedure.     

Locally Ablative Non-surgical Management of Colo-rectal Liver Metastasis

Background

Liver is one of the commonest sites of metastasis in colorectal cancer patients. Solitary liver metastasis or oligometastasis are traditionally treated by surgical resection or chemotherapy.

Discussion

There may be a subgroup of these patients who are not suitable for surgery or chemotherapy due to various co-morbid factors. These patients can be treated by novel minimally invasive or noninvasive ablative techniques like interstitial brachytherapy, extracranial stereotactic radiotherapy, and radiofrequency ablation.     

Peritoneal carcinomatosis is less frequently diagnosed during laparoscopic surgery compared to open surgery in patients with colorectal cancer

Background

During resection of a colorectal tumor a careful inspection of the abdomen should be performed to detect metastases. The aim of the current study was to compare the proportions of patients diagnosed with peritoneal carcinomatosis (PC) during laparoscopic resection (LR) and open resection (OR).

Methods

All patients who underwent resection for colorectal cancer in the Eindhoven Cancer Registry area between 2008 and 2012 were included. Proportions of patients with PC were compared between surgical techniques. Multivariate logistic regression analysis was performed.

Results

6687 Patients underwent resection for colorectal cancer, of whom 1631 patients (24%) underwent LR, 4665 patients (70%) underwent OR. Conversion took place in 391 patients (19% of laparoscopic treated patients). PC was diagnosed in 1.4% of patients undergoing LR, in 5.0% of patients undergoing OR, and in 3.3% of patients in whom LR was converted to OR (p < 0.001). After adjustment for patient and tumor characteristics (e.g., T- and N-stage), patients who were treated by LR had a lower chance to be diagnosed with PC during surgery than patients undergoing OR (odds ratio = 0.42, p < 0.001).

Conclusions

Patients undergoing surgery for colorectal cancer are less frequently diagnosed with PC during LR in comparison to OR. Since effective treatment is currently available for selected patients with PC, a thorough inspection of the peritoneum during surgery is of paramount importance to offer these patients a chance for long-term survival and even cure.     

Complex liver resection for hepatic tumours involving the inferior vena cava

Background

Resection of liver tumours with involvement of inferior vena cava (IVC) is considered to have a high surgical risk.

Aim

We retrospectively reviewed 23 patients who underwent hepatectomy with IVC resection in two West-European liver surgery Units.

Methods

The tumours included liver metastases (n = 13), hepatocellular carcinoma (n = 4), intrahepatic cholangiocarcinoma (n = 3), liver haemangioma (n = 1), primary hepatic lymphoma (n = 1) and recurrent right adrenal gland carcinoma (n = 1).

Results

IVC resection was associated with right hepatectomy in 8 cases, extended right hepatectomy in 9 cases, extended left hepatectomy in 3 cases, minor liver resection in 2 cases, and right hepatectomy with nephrectomy in one case. In 16 patients the IVC wall involvement was <30% of its circumference, and a tangential vena cava resection was performed. In 7 patients (30%) with >50% involvement, a caval segment was resected and replaced with a 20 mm ringed polytetrafluoroethylene graft. R0-resection was achieved in all patients. Median intraoperative blood loss was 1.100 ml (range 490–15,000). Fourteen patients were transfused with a median of 3 PRC units per patient (range 1–25). Major complications occurred in 9 patients. Postoperative stay in ICU was 2.3 ± 3.4 days (range 1–14) and hospital stay was 17.3 ± 2.6 days (range 5–62). In 14 patients, final pathology demonstrated microscopic IVC infiltration.

Conclusions

In selected patients with malignant involvement of the liver and IVC, surgical resection en bloc with IVC is the only possibility to achieve R0 resection, with acceptable mortality and morbidity, in units specialized in liver surgery.     

The Role of Liver-Directed Therapy in Metastatic Colorectal Cancer

Purpose of Review

Colorectal cancer liver metastasis is a major clinical problem, and surgical resection is the only potentially curative treatment. We seek to discuss various liver-directed therapy modalities and explore their roles in the evolving realm of treatment strategies for metastatic colorectal cancer.

Recent Findings

Clinical outcomes for patients with colorectal cancer liver metastases have improved as more patients undergo potentially curative resection and as the armamentarium of systemic treatment and liver-directed therapies continues to expand. Liver-directed therapies have been developed as adjuncts to improve resectability, employed in the adjuvant setting to potentially reduce local recurrence rates, and utilized in the palliative setting with the aim to improve overall survival.

Summary

Ongoing research is expected to validate the role of these evolving therapeutic options, and determine how best to sequence and when to apply these therapies.