© Springer Science+Business Media Dordrecht and People’s Medical Publishing House 2017Xinyu Qin, Jianmin Xu and Yunshi Zhong (eds.)Multidisciplinary Management of Liver Metastases in Colorectal Cancer10.1007/978-94-017-7755-1_2
2. Diagnosis and Treatment of Liver Metastases
Department of Digestive and Oncologic Surgery, Ambroise Paré Hospital Boulogne, Boulogne Cedex, France
The most frequent cause of death in patients with colorectal cancer is due to liver metastases. Approximately 50 % of patients develop liver metastases at some point in the course of their disease, translating into approximately 500,000 patients worldwide . Without any treatment, the median survival of patients with colorectal cancer liver metastases rarely exceeds 1 year, ranging from 3.8 to 21 months. The volume of liver involvement, the presence of extrahepatic disease, the metastatic lymph nodes in the mesentery, the carcinoembryonic antigen (CEA) level, and the age of the patient all influenced the survival rate .
If only a minority of patients with liver metastases is amenable to surgery, surgical resection remains the only treatment that can, to date, ensure long-term survival and cure in some patients . Even if the presence of liver or lung metastases from colorectal cancer is associated with a poor prognosis, it does not always preclude curative treatment.
Recent progress including new chemotherapeutic regimens, ablative techniques, and interventional radiology may permit to increase the number of patients that can be treated with a curative intent. Unfortunately, recurrences are still observed in most patients after resection of liver metastases. To reduce this risk, new therapeutic modalities are based on combined strategy of treatment.
2.2 Diagnosis and Preoperative Assessment of Colorectal Liver Metastases
Clinical symptoms of colorectal liver metastases are usually late occurrences. In most cases, colorectal liver metastases are found during routine radiographic screening leading to the diagnosis of colorectal cancer or during the follow-up after resection of a colorectal primary tumor.
Because hepatic resection is the sole treatment associated with prolonged survival on patient with colorectal liver metastases, the pretherapeutic work-up in patients with colorectal liver metastases should determine whether lesions can be safely and completely removed and whether patients’ conditions allow liver surgery. This work-up should precise the extent of the hepatic and extrahepatic disease, liver function, and comorbidities of the patient that could contraindicate the surgery.
Physical general status of patients has to be assessed before planning surgery. In particular, the question is to determine whether the patient can tolerate general anesthesia, clamping maneuvers required by liver surgery. American Society of Anesthesiologists (ASA) score is a good tool to predict postoperative morbidity and mortality after liver resection and allows selection of patient who can safely undergo liver resection .
Preoperative imaging work-up of liver metastases should precise the respectability of the lesions and is currently based on ultrasound, multiphase helical computed tomography (CT) scan, and magnetic resonance imaging (MRI). These investigations should help to precise the number, the location, and the relationship to major liver vessels, and the distance from the anterior and posterior liver surface of the lesions. Liver metastases should be considered as resectable when all hepatic disease can be safely removed or locally treated leaving sufficient future liver remnant with adequate vascular inflow, venous outflow, and biliary drainage. Number, size, location of primary tumor, and CEA level should not be used as criteria to contraindicate liver resection.
Positron emission tomography–computed tomography (PET-CT) is valuable to rule out an extrahepatic spread of the disease since liver resection should not be performed in case of non-resectable extrahepatic disease [5, 6]. In case of unresectable liver metastases, treatment is initially based on chemotherapy, and imaging work-up is performed every 3 months to evaluate the tumor response and to determine whether a local treatment of the lesions can be considered. In addition, colonoscopy or CT colonography should be performed to exclude a local recurrence or metachronous colorectal neoplasia.
Liver function can be assessed using the Child-Pugh classification, blood liver function tests, and in some cases, the indocyanine green (ICG) retention tests. The volume of the non-tumorous parenchyma that will be left in place after hepatic resection should be evaluated by computed tomography (CT) scan volumetry.
2.3 Surgery for Colorectal Liver Metastases
2.3.1 Intraoperative Assessment
Surgery should start with a careful exploration of the abdominal cavity to rule out an extrahepatic spread of the disease or an unexpected bilobar involvement of the liver which could contraindicate the resection. This exploration includes palpation of the liver and intraoperative ultrasound (IOUS). IOUS is particularly useful to better precise the relationship of the lesions with vascular pedicles and can help to select the type of resection. IOUS can also guide radiofrequency ablation (RFA) of deep lesions in the future liver remnant.
2.3.2 Principles of Liver Resection for Colorectal Liver Metastases
Liver resection should be considered only in a curative intent. To date, there is no data to recommend debulking surgery for colorectal liver metastases. The size of surgical margin for the resection of colorectal liver metastases remains debated. Free surgical margin is an independent prognostic factor survival, and consequently, R0 resection is recommended [7–11].
The extent of liver resection depends on the number, the size, and the location of the lesions. If remnant liver parenchyma is normal, up to six of the eight anatomical segments, i.e., up to 75 % of the liver parenchyma, can be safely resected with low risk postoperative liver insufficiency. However, the majority of patient candidates for a liver resection have received a preoperative chemotherapy that could induce liver damage [12–17].
Liver resections are usually classified in anatomical (i.e., removing one or several segments) or atypical (“wedge”) resections. Oncological results of these two types of resection are similar in the setting of colorectal liver metastases . Resections removing three or more continuous segments are defined as major hepatic resections. Superficial small metastases can be resected with wedge resections. Larger lesions often require major resections.
2.3.3 Increasing the Resectability
Although liver resection is the sole treatment associated with prolonged survival in patients with colorectal liver metastases, only 10–15 % of patients have resectable liver metastases at the time of diagnosis . During the past decades, refinements and improvements of surgical skills have led to extend the frontiers of resectability in patients with colorectal liver metastases .
126.96.36.199 Radiofrequency Ablation
In some cases, curative liver resection can be contraindicated because lesions are bilobar, and the extent of the planned liver resection is too large that could induce postoperative liver failure. Treatment of the lesions located in the future liver remnant can be achieved using tools for local destruction. Cryotherapy of liver metastases has been firstly used in this indication , but in situ recurrence rate was elevated. To date, radiofrequency ablation (RFA) is preferred .
RFA can be performed either percutaneously or intraoperatively. Different types of needle electrode can be used to treat liver metastases. The area of necrosis induced by RFA should be larger than the size of the tumor, by 1 cm, similar to the surgical margin obtained after surgical resection. Tumors of less than 3 cm located in the future remnant liver are currently the better indication of RFA. Indeed, in case tumor of 3 cm or more, oncologic results remain uncertain with the increased risk of in situ local recurrence .
188.8.131.52 Preoperative Portal Vein Embolization
If the future remnant liver after liver resection is too small to provide sufficient postoperative liver function, preoperative selective portal vein embolization has been proposed to induce ipsilateral atrophy and contralateral hypertrophy of the future remnant liver, thus preventing postoperative liver failure . Following embolization, a liver resection judged primarily impossible, due to insufficient volume of remnant liver, is feasible in 60 % of cases, with mortality and morbidity rates comparable to those observed following liver resections without embolization. In case of bilobar lesions, induced liver regeneration or hypertrophy can be associated with an accelerated increase in the size of metastases located in the non-embolized liver . Whether preoperative chemotherapy should be stopped after the embolization to avoid to decrease the hypertrophy of the liver or continued to control the disease during the time interval between the embolization and the hepatectomy is still debated [25–27].
184.108.40.206 Two-Stage Hepatectomy
Multiple bilobar liver metastases are often considered as unresectable. In selected cases, bilobar liver metastases can be resected in two stages. The first stage includes the resection or local destruction of lesions located in the future remnant liver which is in most cases the left liver. The second hepatectomy is generally a right or an extended right hepatectomy. During the first procedure, a right portal vein ligation can be performed if the volume of the left lobe is judged to be insufficient. Although this strategy can only be proposed in selected patients with unresectable liver metastases, oncologic outcome can be close to those observed in patients’ resectable liver metastases .
220.127.116.11 Repeat Liver Resections for Recurrent Metastases
Recurrence limited to the liver following previous hepatic resection occurs in 25–50 % of cases and may be amenable to repeat resection . Postoperative mortality and morbidity do not differ from those reported after a first resection, and the mean survival approaches 2 years. Hepatic recurrences should therefore be resected whenever technically feasible.
18.104.22.168 Preoperative Chemotherapy
In case of resectable liver metastases, preoperative chemotherapy can be administered to decrease the risk of recurrence, to test the chemosensitivity of the tumor, to guide the choice for postoperative treatment, and to facilitate the resection. One randomized trial  has recently showed that perioperative chemotherapy decreases the risk of recurrence after liver resection for resectable colorectal liver metastases (see Chap. 13).
In case of unresectable liver metastases, chemotherapy is initially the sole treatment that can be proposed. During the past decade, the introduction of new cytotoxic agents (camptothecin and oxaliplatin) and targeted therapies (bevacizumab and cetuximab) has led to increase the response rate and survival of patients with advanced colorectal cancer [31–36]. In patients with unresectable liver metastases, in case of tumor shrinkage during chemotherapy, curative liver resection may be considered. Several retrospective studies have showed that oncologic outcome of patients operated of initially unresectable liver metastases downstaged by chemotherapy may be good even in case of initial large hepatic involvement. Recurrence rate is close to 80 % and remains elevated in these patients, and 5-year survival rate can range from 25 to 35 % [20, 37, 38].
2.3.4 Postoperative Outcome
22.214.171.124 Early Postoperative Outcome
In most recent studies, in-hospital mortality rates vary from 0 to 5 % and are strongly influenced by intraoperative blood loss, preoperative liver function, and extent of liver resection . Reversible postoperative complications are observed in 25–40 % of patients. Morbidity after hepatic resection is usually due to transient liver failure, hemorrhage, sub-phrenic abscesses, or biliary fistula. The mean hospital stay after liver surgery ranges from 10 to 15 days in the absence of complications.
Recent studies suggest that administration of preoperative chemotherapy could increase the risk of liver resection for colorectal liver metastases. Morbidity rate may be slightly increased in patients who have received a preoperative chemotherapy [14–16]. The impact of preoperative chemotherapy on postoperative mortality after liver resection is debated, and to date, only one study has reported that chemotherapy could increase the mortality after liver resection. In this study, the mortality rate was increased in patients who had lesions of chemotherapy associated steatohepatitis .
126.96.36.199 Oncologic Results
Liver resection of colorectal metastases is associated with 3- and 5-year survival rates close to 40 % and 30 %, respectively. After resection, recurrences are observed in two-thirds of patients and involve the liver in 50 % of cases.
Several studies have assessed factors influencing survival. Risk factors of recurrence have been identified using multivariate analysis on two large series of more than 1,000 patients [7–9]: age, size of the largest metastasis, elevated CEA level, stage of the primary tumor and lymph node involvement, disease-free interval <12 months, number of liver nodules, and involved surgical margin. However, these studies did not take into account the potential impact of associated treatment and in particular the administration of chemotherapy.
2.4 Treatment Strategy for Colorectal Liver Metastases
Although liver resection allows prolonged survival in a subset of patients with colorectal liver metastases, recurrences are still observed. Recurrence rate after hepatectomy approaches two third. To decrease the risk to tumor relapse, combined strategy using chemotherapy before, after, or both in association with surgery has been proposed.
2.4.1 Results of Combined Therapeutic Strategies for Colorectal Liver Metastases
Adjuvant treatment has firstly been evaluated for the treatment of resected colorectal liver metastases. Efficacy of postoperative treatment using systemic chemotherapy or hepatic arterial infusion with 5-FU, folinic acid, or floxuridine has been tested after resection of liver metastases from colorectal cancer (CRC) in several randomized studies [43–47], but survival benefit has not yet been clearly demonstrated. These data have been confirmed in a recent meta-analysis that showed that adjuvant CT with a 5-FU-based regimen versus no postoperative chemotherapy tends to improve disease-free and overall survival after complete resection of CRC metastases, but the observed improvement in survival was not statistically significant .