Upfront Resectable Patients
The place of chemotherapy needs to be discussed in patients presenting upfront resectable CLM. On one hand, a preoperative chemotherapy may treat potential micrometastases, test the chemotherapy and serve as a selection tool68 (nonresponders to chemotherapy would be unsuitable candidates for surgery28). On the other hand, a preoperative treatment may induce toxicity of the nontumoral liver, associated with increased morbidity,69 and may cause the complete radiologic response which turns to be problematic since persistent microscopic disease or recurrence in situ was observed in 83% of these so-called “missing metastases.”70
To date, only one randomized trial71 has investigated the role of perioperative oxaliplatin-based chemotherapy (six cycles before and after resection in the perioperative chemotherapy vs. no chemotherapy) in patients operated on for resectable liver disease with up to four CLM. The authors found that perioperative chemotherapy was associated with a better disease-free survival (42% vs. 33% at 3 years). However, a recent update of these results has shown no benefit in overall survival with perioperative chemotherapy. Noteworthy, 23% of patients of the perioperative chemotherapy arm did not receive postoperative chemotherapy. Moreover, the postoperative morbidity was significantly higher in patients who received chemotherapy (25% vs. 16%).
In view of these results, perioperative chemotherapy should be given in patients with resectable multiple metastases. However, the real benefit of preoperative chemotherapy has been questioned by a large multicentric study showing that in the subgroup of patients presenting a single metachronous liver metastasis, preoperative chemotherapy did not influence overall survival.72
Initially Unresectable But Potentially Resectable CLM: How to Increase Resectability?
In these patients, the strategy pursues one single goal: to render the hepatic disease suitable for resection (Fig. 128-3). Two different means can lead to this objective: (i) an optimal preoperative systemic treatment which induce the morphologic response required for secondary surgery and (ii) interventional radiological and surgical refinements which enable complex and extended hepatectomies.
A, B. CLM at diagnosis. C, D. CLM after downsizing induced by chemotherapy.
In this situation, the chemotherapy plays a crucial role since only good responders to chemotherapy will become suitable for surgery and consequently may have a chance of long survival.
The development of modern protocols combining 5-FU-leucovorin with either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) has improved survival of unresectable patients compared to 5-FU alone. These two regimens used have been shown to be equivalent in terms of outcome73 and to induce a morphological response rate of around 50%. This is of major importance as response rate to systemic treatment strongly correlates the rate of conversion to surgery.74 The morphological response can be increased by adding a monoclonal antibody, either directed against the vascular endothelial growth factor (VEGF; bevacizumab)75,76 or against the epidermal growth factor receptor (EGFR; cetuximab, panitumumab).77,78 Because bevacizumab has an antiangiogenic effect, a 4- to 6-week interval between its last administration and surgery is usually recommended. However, bevacizumab does not seem to impair liver regeneration or increase surgical morbidity79,80 or even to result in major increase of local complications related to the primary tumor.81 The administration of anti-EGFR therapies requires to assess the mutational status of the RAS oncogene family (KRAS exon 2, 3, 4, BRAF exon 15, NRAS exon 2, 3, 4) since there is evidence that patients mutated for these genes (about half of patients) will not respond to anti-EGFR therapies.78
A protocol associating irinotecan, oxaliplatin, and 5-FU/leucovorin (FOLFOXIRI) in first-line has shown better progression-free and better overall survival at 5 years.82 Targeted therapies could be safely associated with this protocol.83,84
The conversion rate to resectability reported in the literature ranges from 2% to 46% due to difference in definitions, surgical experience, or associated chemotherapy regimens.85
The optimal regimen remains a controversial issue. However, considering the importance of the response to chemotherapy, our policy is to maximize the first-line treatment in patients with potentially resectable CLM to increase their chance to become resectable. A recent multidisciplinary international consensus recommended as optimal conversion chemotherapy the use of doublets (FOLFOX or FOLFIRI) combined with targeted therapy or the use of triplet (FOLFOXIRI) combined or not with targeted therapy.34
Hepatic Arterial Infusion
The use of chemotherapy (floxuridine and dexamethasone) administered through the hepatic artery by a catheter placed radiologically or surgically plus systemic chemotherapy (oxaliplatin and irinotecan) has been shown to increase the secondary resectability rate.86 Goere et al87 reported that the hepatic arterial infusion (HAI) of oxaliplatin with systemic 5-FU and leucovorin allows complete CLM resection in 24% of patients with unresectable hepatic disease at diagnosis. HAI was more efficient when administered as first-line therapy, but also appears to induce response in oxaliplatin-resistant patients. The 5-year overall survival was 56% in resected patients versus nil in the nonoperated patients.
Considering the high probability of remaining viable cancer cells in metastases exhibiting complete morphological response,70 the extent of LR should be performed in a way to encompass the area previously involved by CLM having disappeared under chemotherapy. Deep and small lesions at high risk of disappearing can be marked by coils.88 This is unnecessary for small peripheral lesions, where radiologic disappearance is associated with capsular retraction making possible intraoperative localization. In case of complete radiological response to chemotherapy, that is, total disappearance of initial metastases, there is no consensus about the ideal strategy: to operate on an intention to resect residual deposits which could have been misdiagnosed by preoperative imaging or to adopt a “wait and see” policy with the perspective to perform surgery in case of reappearance of the initial metastases.
Chemotherapy-Associated Liver Injury
Preoperative chemotherapy has been demonstrated to be a risk factor of morbidity after hepatectomy.89 Postoperative events seem to be related to different microscopic lesions of the nontumoral liver observed after systemic chemotherapy: severe oxaliplatin-induced lesion (sinusoidal obstructive syndrome (SOS), nodular regenerative hyperplasia)90 and steatohepatitis (after irinotecan-based regimen).91 Some studies have reported that SOS was a risk factor of liver failure after major hepatectomy92 and steatohepatitis was associated with higher postoperative mortality.93 High rate of indocyanin green retention,94 indirect signs of portal hypertension (low serum platelets level, splenomegaly95), and aspartate aminotransferase to platelet ratio index (APRI) score96 are useful tools to predict severe SOS. These damages could be reversible with the cessation of oxaliplatin within a few weeks. In presence of arguments in favor of chemotherapy-associated lesion, precautions should be undertaken regarding the volume of the FRL.
It is estimated that about 60% of patients who underwent a curative resection of CLM will further develop intrahepatic or extrahepatic recurrence. Of them, 30% will present recurrence involving the liver only. Several retrospective studies have shown that a second hepatectomy yielded similar long-term outcome than after a first hepatectomy without additional morbidity.97 Comparable results were observed in series of patients who underwent a third hepatectomy98 or even repeated lung metastasectomy.99 This demonstrates that iterative hepatic resections are feasible and safe, and provide excellent oncological outcome. In practice, this aggressive attitude was performed in selected patients, based on response to chemotherapy. This emphasizes the need for efficient perioperative chemotherapy, the cornerstone of the “oncosurge” management.
Place for Liver Transplantation
Oncological results of liver transplantation (LT) are widely acceptable in cirrhotic patients with hepatocellular carcinoma.100 Promising outcomes have been reported in other liver malignancies such as hilar cholangiocarcinoma101 and neuroendocrine liver metastases.102 Contrary to these neoplasms, CLM were considered until recently as an absolute contraindication for LT, based on poor results after LT in old series. However, the emergence of efficient systemic treatment which enables a better control of the disease, the improvement in the accuracy of imaging studies to detect extrahepatic disease, and the recent development of drug which associates immunosuppressive and antiproliferative properties have questioned the relevance of LT in unresectable patients. The role of LT to treat patients with unresectable CLM without extrahepatic disease was investigated by a pilot study103 led in Norway, a country characterized by a very short waiting time period due to a favorable donor situation. Twenty-one patients were transplanted. The 5-year overall survival after LT was 60% after a median follow-up of 27 months, with a median disease-free survival of less than 1 year. Most recurrences occurred in the lung and could be treated repeatedly by surgery with a curative intent. Noteworthy, progression while on chemotherapy was associated with poor outcome. The outcomes reported in this series suggest that LT may have a place in highly selected patients with an unresectable disease confined to the liver. Further studies are required to precise the role of LT in this very particular indication.
The Global Therapeutic Strategy
Before setting the therapeutic strategy, physicians must provide answers to several questions:
Is the hepatic disease resectable?
Is there extrahepatic metastatic disease? If yes, is it resectable?
Is the primary tumor still in place?
If yes, are there any symptoms (bleeding, occlusion)?
If yes, does this require a neoadjuvant treatment?
The physical condition of the patient needs to be taken into consideration when planning the therapeutic strategy.
The management is summarized by the decisional algorithm, as shown in Fig. 128-4.
Simplified decisional algorithm for management of CLM. FOLFIRI, 5-fluorouracil/leucovorin plus irinotecan (CPT-11); FOLFOX, 5-fluorouracil/leucovorin plus oxaliplatin; FOLFOXIRI, tritherapy with 5-fluorouracil/leucovorin, irinotecan, and oxaliplatin.*Anti-VEGF: bevacizumab; anti-EGFR:cetuximab, panitumumab (super wild type patients).