Surgery has evolved to become the standard of care for a defined subset of patients with hepatic colorectal metastases. Hepatic resections are now well-controlled procedures, with several centers reporting very low perioperative mortality rates.
The article by Drs. Ravikumarand Gallos provides an excellent and timely overview of recent developments in the treatment of metastaticliver disease.
Value of Resectional Surgery
Surgery has evolved to become the standard of care for a defined subset ofpatients with hepatic colorectal metastases. Hepatic resections are nowwell-controlled procedures, with several centers reporting very lowperioperative mortality rates. Although the majority of patients who undergohepatic resection still succumb to metastatic disease, the authors providestrong data in support of hepatic resection as a means of prolonging survivalbeyond that expected with systemic or regional chemotherapy alone. In addition,three large single-institution series have reported high tumor-free survivalrates after 5 years, thus providing the best presumptive evidence of potentialcure from resection.[1-3]
Criteria for Resection
A clear distinction should be made between the factors predicting prognosisfollowing hepatic resection for colorectal metastases and the criteriacontraindicating resection. The three major factors affecting outcome afterresection are (1) a positive surgical resection margin, (2) a synchronous tumorpresentation (liver and primary), and (3) a node-positive primary.[1,3-7] Theonly two contraindications to resection are the presence of extrahepatic diseaseand the inability to achieve complete resection.
Although the presence of four or more metastases was once thought to precludelong-term survival, the absolute number of metastases no longer contraindicatesresection. Similarly, bilobar disease is no longer considered a contraindicationto operative intervention. The inability to achieve a negative margin isconsidered an absolute contraindication to resection, but the 5-year survival ofpatients with margins < 1 cm is greater than 20% and justifies hepaticresection as long as a negative margin is obtained.[8,9]
The term extrahepatic disease should be clarified. We agree with the authors’statement that lymph node metastases contraindicate resection because thesemetastases are either hepatic (hilar and celiac lymphadenopathy) or advancedfrom primary colorectal cancer (periaortic and iliac lymphadenopathy). However,extrahepatic disease encompasses a broad spectrum of clinical presentations thatper se do not contraindicate combined hepatic and extrahepatic resection,because extended survival has been reported after complete resection for
(1) Contiguous extension of tumor to adjacent anatomic structure (adrenalgland, diaphragm, or major vessel such as portal vein or vena cava[1,10,11]
(2) The recently described intraluminal extrahepatic bile duct extension ofcolorectal metastasis as tumor thrombus[8,12]
(3) Local or locoregional recurrence near the site of resection of primarycolorectal cancer, assuming this is unresected residual disease
(4) Limited metastatic disease (one or, perhaps, two metastases) at distantorgan sites (such as the lung or pancreas).[11,13]
Hepatic Functional ReserveAfter Resection
For reasons as yet unclear, hepatic colorectal metastases rarely occur in thesetting of viral hepatitis and cirrhosis.[14-16] In contrast, significantsteatosis is not rare, and the associated morbidity and mortality of surgicalresection are significantly increased.[17,18] In this regard, cryoablation andradiofrequency ablation represent novel alternatives for patients at high riskfor resection and should be part of the armamentarium to treat these patients.We disagree with the authors’ assertion that "up to 85% of healthy livermay be removed with impunity," because the minimal safe remnant livervolume for extended resection remains a subject for debate. Recent evidencesuggests that resections of more than 75% are associated with increasedmorbidity and length of hospital stay.
Percutaneous preoperative portal-vein embolization is an option if there isconcern regarding possible postoperative complications due to a small liverremnant. The procedure induces atrophy of the embolized tumor-bearing liver andhypertrophy of the contralateral nontumorous liver. Moreover, the strategyis associated with minimal morbidity, and hypertrophy of the anticipated liverremnant is achieved in 3 to 4 weeks. At M. D. Anderson Cancer Center,hepatic volumetric measurements are now performed routinely if a small-remnantliver is anticipated, to determine the need for preoperative portal-veinembolization.
Although the authors express concern regarding the use of postoperativechemotherapy based on an experimental model of liver resection, there is noclinical evidence to support this consideration. Following hepaticresection, chemotherapy is usually not initiated prior to the normalization ofliver function tests. Although there is no randomized prospective studycomparing systemic adjuvant chemotherapy to no chemotherapy after liverresection, recent retrospective data indicate that adjuvant systemicchemotherapy (fluorouracil [5-FU] and leucovorin) is an independent predictor offavorable outcome following resection. With the advent of newer agents suchas irinotecan (CPT-11, Camptosar) and oxaliplatin, researchers have a renewedinterest in delivering systemic chemotherapy before or after resection, in aneffort to further improve survival. More investigation of these strategies isneeded in the context of well-designed clinical trials.
Kemeny et al recently reported a randomized study that compared patients whoreceived regional fluorodeoxyuridine and dexamethasone via an implantable pumpas well as systemic 5-FU and leucovorin (combined therapy) to patients receivingsystemic 5-FU and leucovorin alone (monotherapy) after liver resection. Asignificant difference between arms was seen in 2-year (86% vs 72%,P = .03) and hepatic disease-free survival (90% vs 60%, P <.001).
An Eastern Cooperative Oncology Group prospective randomized trial compared56 patients randomized to hepatic resection alone with 53 patients randomized tohepatic resection followed by hepatic artery chemotherapy withfluorodeoxyuridine for four cycles and systemic 5-FU for 12 cycles.Preliminary analysis showed the 3-year recurrence-free rate was 34% for thesurgery alone group and 58% for the patients receiving adjuvant chemotherapy (P< .05), but 5-year survival was not significantly different between the twoarms.
These studies did not include the use of newer agents (irinotecan oroxaliplatin) that have been found effective in the treatment of advancedmetastatic colorectal carcinoma. Because of a lack of definitive data regardinghepatic artery chemotherapy infusion after liver resection, and given theavailability of effective new drugs delivered systemically, we recommend the useof hepatic artery chemotherapy after resection only as part of investigationalstudies.
A Multidisciplinary Process
The authors discuss the need for accurate imaging and assessment of resectionmargins, and the ongoing interest in the use of adjuvant therapies, but they donot explicitly express the need for a multidisciplinary team in this setting.This is an important prerequisite for a successful program in hepatic resectionof metastatic disease, irrespective of the primary site.
At M. D. Anderson, a dedicated team of surgeons, radiologists,pathologists, and medical oncologists routinely discuss patients prior tosurgical intervention. Individualized treatment planning occurs as a multistepprocess in the pre-, intra-, and postoperative settings. As a general rule,because hepatic resection may result in local and/or distant failure, we havegenerally advocated the use of systemic therapy for 2 to 3 months prior tosurgical intervention. This allows the identification of patients with rapidlyprogressing resistant disease who will not ultimately benefit from resection. Inaddition, it provides an in vivo chemosensitivity test to help guidepostoperative chemotherapy delivered either regionally or systemically.
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