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Combination of surgery and chemotherapy and the role of targeted agents in the treatment of patients with colorectal liver metastases: recommendations from an expert panel.


The combination of chemotherapy and surgery is currently accepted as the way forward for improving survival in patients with initially unresectable colorectal liver metastases Metastasis (plural, metastases)
A tumor growth or deposit that has spread via lymph or blood to an area of the body remote from the primary tumor.

Mentioned in: Malignant Melanoma
. Standard combination chemotherapy regimens Chemotherapy regimens are often identified with acronyms, identifying the agents used in combination. Unfortunately, the letters used are not consistent across regimens, and in some cases (for example, "BEACOPP") the same letter is used to represent two different treatments.  comprising 5-fluorouracil (5-FU) plus leucovorin [LV, also known as folinic acid folinic acid /fo·lin·ic ac·id/ (fo-lin´ik) leucovorin; the 5-formyl derivative of tetrahydrofolic acid; it can act as a coenzyme carrier in certain folate-mediated reactions and is used, as the calcium salt leucovorin calcium, in the  (FA)] in combination with irinotecan, typically FOLFIRI FOLFIRI Folinic Acid, Fluorouracil & Irinotecan (chemo treatment)  or oxaliplatin (FOLFOX FOLFOX 5-Fluorouracil, Leucovorin and Oxaliplatin (chemo treatment) ) have been reported to facilitate the resection of 9%-40% of initially unresectable metastases [1, 2], with data emerging from randomized ran·dom·ize  
tr.v. ran·dom·ized, ran·dom·iz·ing, ran·dom·iz·es
To make random in arrangement, especially in order to control the variables in an experiment.
 trials suggesting that the addition of targeted agents and a third cytotoxic cy·to·tox·ic
Of, relating to, or producing a toxic effect on cells.

 might be even more effective.

Overall, however, there is a paucity of randomized trial data in this clinical setting, and the wide differences in the liver resection Liver resection refers to the removal of the whole liver (which would be fatal in a living person) or one or more of its vascular segments. It is commonly done as a treatment for malignant tumors, such as hepatoma (liver cancer) or metastases from other cancers.  rates reported for different trials in large part reflect the differences in the criteria for resectability/unresectability that exist between the different treatment centers and surgeons, in the absence of a clear definition. This in turn impacts on the assessment of outcome. Other identified shortcomings A shortcoming is a character flaw.

Shortcomings may also be:
  • Shortcomings (SATC episode), an episode of the television series Sex and the City
 in these studies included inadequate staging, the need for improved patient work-up and poor patient selection, coupled with concerns over chemotherapy-induced liver damage [1,2]. The pattern of use and timing of administration of chemotherapy are also an issue, with some patients receiving chemotherapy only before surgery, some only after surgery and some both before and after surgery.

Typically, the liver surgeon is faced with three clinical scenarios when assessing patients with colorectal liver metastases:

(i) patients with readily resectable re·sect·a·ble
Suitable for resection.
 metastatic Metastatic
The term used to describe a secondary cancer, or one that has spread from one area of the body to another.

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pertaining to or of the nature of a metastasis.

(ii) metastatic disease that is initially considered to be unresectable, principally due to location and

(iii) those patients that are unlikely ever to become resectable [1].

Current treatment practice is likely to be surgery for resectable liver disease Liver Disease Definition

Liver disease is a general term for any damage that reduces the functioning of the liver.

The liver is a large, solid organ located in the upper right-hand side of the abdomen.
 and palliative chemotherapy for those patients with initially unresectable and unlikely to ever become resectable disease. In any assessment of which chemotherapy regimen is best, there needs to be improved patient classification/staging, to facilitate, for example, a degree of cross-trial comparison in a clinical setting where few randomized trials are likely to be conducted and where resectability is such a subjective clinical end point. A new 'grid' staging system Staging system
A system based on how far the cancer has spread from its original site, developed to help the physician determine how best to treat the disease.

Mentioned in: Neuroblastoma
 has been proposed that if adopted would allow stratification of patients from the outset, in terms of potential resectability, while at the same time helping to direct their therapeutic management [1,3]. The advantages of such a staging system would be to alert physicians early to the possibility of 'curative intent' strategies and to provide a clear indication of therapeutic strategy. The ultimate aim would be to facilitate the better stratification of patients for clinical trials. This is particularly important as going forward there are likely to be more first-line randomized studies where resection rate is part of the analysis.

This manuscript presents the consensus clinical recommendations on the use of chemotherapy as an adjunct to surgery in the treatment of patients with colorectal liver metastases, arrived at by an expert group of 21 surgeons and medical oncologists at the Sixth International Colorectal Liver Metastases Workshop. Consideration was given to improving the definition of unresectability, clarifying the impact of chemotherapy-induced liver damage on clinical outcome and defining the best regimens for each treatment setting. In particular, consideration was given to when and where to use specific chemotherapy regimens with or without targeted agents in the treatment of patients with:

(i) initially resectable liver disease (resectable metastases) and

(ii) initially unresectable liver disease (unresectable metastases, comprising both those potentially resectable after tumor regression and unlikely ever to become resectable categories), and relevant trial end points.

Toward a clear definition of unresectability

It is clear that the 4- and 5-year survival rates now attainable for patients with colorectal liver metastases are effected by a combination of surgery and chemotherapy [1,2,4]. Historically, liver metastases were classified as unresectable if they were large in size, poorly located, multinodular or there was evidence of extrahepatic ex·tra·he·pat·ic  
Originating or occurring outside the liver.
 disease [5-7], but even today the criteria differ from center to center and country to country [5,8-10]. For example, in 2004, the eligibility criteria for the pivotal EORTC EORTC European Organization for Research and Treatment of Cancer  40983/EPOC intergroup in·ter·group  
Being or occurring between two or more social groups: intergroup relations; intergroup violence. 
 study included 'up to four resectable liver metastases'. The limitation to four visible metastases, however, was not meant as a definition of resectability but only as a clear criterion for inclusion [10]. In 2007, Figueras et al. [4] published a study where no predefined criteria of resectability were cited with regard to number or size of tumors, locoregional invasion or extrahepatic disease. The only prerequisite was that resection had to have the potential to be complete and macroscopically mac·ro·scop·ic   also mac·ro·scop·i·cal
1. Large enough to be perceived or examined by the unaided eye.

2. Relating to observations made by the unaided eye.
 curative [4]. Nowadays, it is accepted that experienced surgeons can carry out all kinds of operations, including multiple resections, provided that there is sufficient remnant liver (>30%) and surgery is not too risky due to location (proximity to vessels of the anticipated remnant liver). Other considerations must include the presence of questionably resectable extrahepatic disease and poor tumor biology. However, age is not a contraindication contraindication /con·tra·in·di·ca·tion/ (-in?di-ka´shun) any condition which renders a particular line of treatment improper or undesirable.

 to liver resection in fit patients although mortality of course is higher just because of old age: 4.5% versus 1.5% for patients >70 and <70 years, respectively [11].

The general consensus of the panel was that there will never be a perfect definition of resectability because of the extremely diverse patterns of disease presentation. However, it was accepted that where possible it was better to remove a metastasis metastasis /me·tas·ta·sis/ (me-tas´tah-sis) pl. metas´tases  
1. transfer of disease from one organ or part of the body to another not directly connected with it, due either to transfer of pathogenic microorganisms or to
 than to leave it in situ In place. When something is "in situ," it is in its original location.  and that going forward R1 resections may become an acceptable clinical strategy provided that they confer meaningful patient benefit.

Liver damage following chemotherapy

Histological lesions are known to occur in the liver following chemotherapy with the type of lesion being dependent on the chemotherapy the patient is receiving [12-15]. Vascular lesions can be observed after administration of oxaliplatin-based chemotherapy. Analysis of the impact of vascular lesions on outcome suggests that morbidity and mortality Morbidity and Mortality can refer to:
  • Morbidity & Mortality, a term used in medicine
  • Morbidity and Mortality Weekly Report, a medical publication
See also
  • Morbidity, a medical term
  • Mortality, a medical term
 after liver surgery are not increased in patients with sinusoidal sinusoidal /si·nus·oi·dal/ (si?nu-soi´dal)
1. located in a sinusoid or affecting the circulation in the region of a sinusoid.

2. shaped like or pertaining to a sine wave.
 lesions but in the case of the most severe vascular lesions (hemorrhagic Hemorrhagic
A condition resulting in massive, difficult-to-control bleeding.

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pertaining to or characterized by hemorrhage.
 centrilobular necrosis, regenerative nodular nodular

marked with, or resembling, nodules.

nodular dermatofibrosis
see dermatofibrosis.

nodular episcleritis
see nodular fasciitis (below).

nodular fasciitis
a firm painless nodular swelling, 0.
 hyperplasia), there is a higher risk of operative bleeding and a transfusion requirement [14,16]. Analysis of the impact of steatosis steatosis /ste·a·to·sis/ (ste?ah-to´sis) fatty change.

See fatty degeneration.


fatty degeneration. See also muscular steatosis.
 on outcome suggests that morbidity is increased but not mortality and that there is an increased rate of infectious complications [17,18]. While steatohepatitis linked to irinotecan treatment may be associated with increased 90-day mortality due to liver failure liver failure Clinical medicine Liver insufficiency that results in death, requires a liver transplant, or is characterized by recovery after encephalopathy, or while awaiting a transplant; also defined as a condition with ≥ 3 of following: albumin < 3.  after surgery [14]. However, this has not been reported in other studies and many question whether this finding in this study was not related to the duration of treatment [14].

Two studies, however, clearly show that the morbidity rate morbidity rate
The proportion of patients with a particular disease during a given year per given unit of population.

morbidity rate Epidemiology The number of cases of a particular disease in a unit of population
 is related to the number of cycles of chemotherapy administered [16,19]. Also, more recently, data on the postoperative complications postoperative complications, unexpected problems that arise following surgery. The most frequent are bleeding, infection, and protracted pain.
 for the two patient groups in the EORTC 40983/EPOC study showed 3 months of preoperative pre·op·er·a·tive
Preceding a surgical operation.


preceding an operation.

preoperative care
the preparation of a patient before operation.
 chemotherapy with FOLFOX-4 to impact relatively modestly on surgical outcome. In this study, postoperative complications were more frequent in patients who had received chemotherapy and resulted mainly in a prolongation of hospital stay and were reversible. Only one patient out of 180 was refused surgery due to liver damage [10]. The panel also considered the possible effects of the antiangiogenic an·ti·an·gi·o·gen·ic
Inhibiting the growth of blood vessels.

 agent bevacizumab on liver resection amid concerns that targeting the vascular endothelial growth factor Vascular endothelial growth factor (VEGF) is an important signaling protein involved in both vasculogenesis (the de novo formation of the embryonic circulatory system) and angiogenesis (the growth of blood vessels from pre-existing vasculature).  (VEGF VEGF vascular endothelial growth factor. ) may augment chemotherapy-induced hepatic lesions and diminish regeneration after resection. Data from one study showed there to be no major effect of bevacizumab on the incidence of postoperative complications if stopped at least 5 weeks prior to surgery [20]. These data were confirmed by a study of 64 hepatectomies carried out in the United States United States, officially United States of America, republic (2005 est. pop. 295,734,000), 3,539,227 sq mi (9,166,598 sq km), North America. The United States is the world's third largest country in population and the fourth largest country in area.  [21], a retrospective analysis of 96 patients which suggested a bevacizumab break of 8 weeks before surgery [22], and by data from the phase IV First BEAT trial [23]. The overall consensus was that neo-adjuvant chemotherapy can induce liver damage but that there are few clinical consequences if patients are not overtreated. Furthermore, bevacizumab treatment appears to be manageable in this treatment setting provided that proper care is taken.

The case for adjuvant therapy Adjuvant therapy
A treatment done when there is no evidence of residual cancer in order to aid the primary treatment. Adjuvant treatments for endometrial cancer are radiation therapy, chemotherapy, and hormone therapy.

In the United States and Europe, chemotherapy is often administered following liver resection, although the benefit has not been formally demonstrated in clinical trials. It is seen, however, as being a logical extension of the benefit reported for adjuvant therapy in stage III colon cancer colon cancer, cancer of any part of the colon (often called the large intestine). Colon cancer is the second most common cancer diagnosed in the United States.  [24, 25], as there are very few randomized studies of adjuvant therapy after liver resection [26-30]. In the multicenter, phase III Noun 1. phase III - a large clinical trial of a treatment or drug that in phase I and phase II has been shown to be efficacious with tolerable side effects; after successful conclusion of these clinical trials it will receive formal approval from the FDA , FFCD FFCD Fédération Francophone de Carcinologie Digestive  ACHBTH AURC 9002 trial, 173 patients were randomized to either R0 resection plus observation or R0 resection plus 6 months bolus bolus /bo·lus/ (bo´lus)
1. a rounded mass of food or pharmaceutical preparation ready to swallow, or such a mass passing through the gastrointestinal tract.

2. a concentrated mass of pharmaceutical preparation, e.
 5-FU/LV starting days 10-35 after surgery [30]. The 5-year disease-free survival disease-free survival Oncology The time that a person with a disease lives without known recurrence; DFS is major clinical parameter used to evaluate the efficacy of a particular therapy, which is usually measured in 'units' of 1 or 5 yrs. See Cure, Remission.  (DFS (Distributed File System) An enhancement to Windows NT/2000 and 95/98 that allows files scattered across multiple servers to be treated as a single group. With Dfs, a network administrator can build a hierarchical file system that spans the organization's LANs and ) rates were 27% and 34% for observation only versus chemotherapy, respectively. The difference was not statistically significant in univariate analysis, but Cox multivariate analysis multivariate analysis,
n a statistical approach used to evaluate multiple variables.

multivariate analysis,
n a set of techniques used when variation in several variables has to be studied simultaneously.
 showed a positive effect of chemotherapy. There was also a trend toward increased overall survival (OS) in those patients receiving chemotherapy. Combination of these results with those of the EORTC/NCIC CTG/GIVIO trial [29], which had a similar design (see Table 1), demonstrated a clear trend in terms of both progression-free survival (PFS PFS,
n post facilitation stretch; therapeutic approach utilized during proprioceptive neuromuscular facilitation in which the patient begins the stretch midway between the fully relaxed and fully stretched position and uses maximum level of effort to
) and OS in favor of the chemotherapy arm but again this was not statistically significant [31]. However, multivariate analysis of the pooled data has shown chemotherapy to be a statistically significant prognostic factor prognostic factor Medtalk Any factor–eg, Pt age, family Hx, lifestyle, stage of presentation, that is weighed in determining a prognosis. See Prognosis. . Retrospective analysis of data from the United States and Europe shows better survival in those patients receiving adjuvant therapy after resection of colorectal liver metastases, lending still further support to this idea [32,33]. A randomized Phase III trial comparing infused 5-FU/LV versus FOLFIRI as adjuvant adjuvant /ad·ju·vant/ (aj?dbobr-vant) (a-joo´vant)
1. assisting or aiding.

2. a substance that aids another, such as an auxiliary remedy.

 treatment following R0 resection of colorectal liver metastases has reported a median DFS of 24.7 and 21.6 months for FOLFIRI and 5-FU/LV, respectively. The 1- and 2-year survivals were 77% and 51% versus 63% and 46% for FOLFIRI and 5-FU/LV, respectively [34]. The recommendation of the panel was therefore that adjuvant chemotherapy Adjuvant chemotherapy
Treatment of the tumor with drugs after surgery to kill as many of the remaining cancer cells as possible.

Mentioned in: Neuroblastoma
 following liver resection should be considered an option in resected patients, particularly for those patients who did not receive preoperative chemotherapy.

Unresectable colorectal liver metastases

Combination chemotherapy, typically infused 5-FU/LV, in combination with either irinotecan or oxaliplatin but also triple cytotoxic drug cytotoxic drug Oncology An anticancer drug which acts by killing or preventing the cell division Adverse effects Damage to noncancerous tissues or organs with a high proportion of actively dividing cells–eg, BM, hair follicles, GI tract, thereby limiting the  therapy, e.g. FOLFOXIRI, and more recently combination chemotherapy regimens with the targeted agents cetuximab and bevacizumab, can render initially unresectable metastases resectable in patients with advanced colorectal cancer colorectal cancer

Malignant tumour of the large intestine (colon) or rectum. Risk factors include age (after age 50), family history of colorectal cancer, chronic inflammatory bowel diseases, benign polyps, physical inactivity, and a diet high in fat.
 (CRC (Cyclical Redundancy Checking) An error checking technique used to ensure the accuracy of transmitting digital data. The transmitted messages are divided into predetermined lengths which, used as dividends, are divided by a fixed divisor. ) [1,2]. Although this review will focus on liver metastases and liver surgery, the presence of extrahepatic disease no longer precludes surgery provided that it is also resectable [1,35]. Today, resection rates approaching 20% are rapidly becoming the norm in small single-center and singlearm studies depending on patient selection [1]. As a consequence, 5-year survivals of 50%, after combined treatment, are becoming increasingly common [4]. Current treatment practice for patients with initially unresectable metastatic disease is to treat with the most effective regimen, in terms of response rate and PFS that the patient can tolerate [1], coupled with the recommendation that surgery should be conducted as early as possible to minimize the effects of chemotherapy on the liver.

So the question then becomes 'what defines the most active regimen in this clinical setting?' In an ideal world, it would be hoped that 'neo-adjuvant' chemotherapy in patients with colorectal liver metastases would not only shrink the tumor but also reduce the recurrence/relapse rate by killing any micrometastases that might remain after surgery. Since response rate correlates with resection rate [36], regimens that could be selected based on present knowledge are FOLFIRI/FOLFOX alone, these regimens plus a biologic [1,2] or triple cytotoxic drug therapy in patients with good performance status [37,38]. The efficacy of FOLFOX has been demonstrated in large single-center series [6,39-41] and today both FOLFIRI and FOLFOX are considered to be effective in facilitating hepatic resections in single-arm studies in selected patients [9,42,43]. Increasingly, however, the trend may well be toward the use of three active agents in the form of either combination cytotoxic therapy plus a biologic or three cytotoxics. Certainly, data are beginning to emerge from randomized trials (CRYSTAL and OPUS) [44,45] of the added benefit conferred by the targeted agent cetuximab on the response rates and resection rates achieved with standard first-line therapies in patients with advanced CRC. In the phase III CRYSTAL trial, CRC patients with unresectable metastases were randomized to receive FOLFIRI[+ or -]cetuximab until disease progression, unacceptable toxicity or withdrawal of patient consent. The addition of cetuximab to FOLFIRI reduced the risk of progression compared with FOLFIRI alone and increased the overall response rate (ORR) compared with the FOLFIRI-alone arm (Table 2) [45]. The rate of surgery with curative intent was also higher in the cetuximab plus FOLFIRI arm compared with the FOLFIRI-alone arm and the R0 resection rate was increased (Table 2) [45].

In two studies, cetuximab conferred an increase in response rate and an increase in resection rate over standard chemotherapy alone, with the benefits being greatest for those patients with KRAS KRAS Knowledge Representation for Autonomous Systems  wild-type tumors; CRYSTAL 59% versus 43% and OPUS 61% versus 37% (Table 2) [46,47]. In a small randomized phase II multicenter study of cetuximab plus FOLFOX or cetuximab plus FOLFIRI in the neo-adjuvant treatment of nonresectable colorectal liver metastases confined to the liver (the CELIM CELIM Organizzazione di Volontariato Internazionale Cristiano  study), response rates of 85% and 66% were reported in the FOLFOX6 and FOLFIRI arms, respectively [48]. In a combined analysis of both arms, the 67 patients with wild-type KRAS tumors achieved a response rate of 79%. Forty percent of FOLFOX6 plus cetuximab patients underwent resection (37% R0), compared with 43% (35% R0) of FOLFIRI plus cetuximab patients and 43% (34% R0) of patients with KRAS wild-type tumors. The high response rates and high resection rates in this study tentatively suggest that cetuximab may increase the possibility of resection for patients with liver metastases. However, no conclusions can be drawn about the contribution of KRAS mutational status to the efficacy outcomes in this study. If the cetuximab data are compared with the data available for bevacizumab in combination with FOLFOX/XELOX in the NO16966 trial [49], bevacizumab had a significant effect on PFS (9.4 versus 8.0 months, P=0.0023) and increased the R0 resection rate slightly (6.3% versus 4.9% and 12.3% versus 11.5% for those patients with liver-limited metastases) but had no effect on response rate [49,50]. Other considerations when choosing a treatment strategy include the requirement for a delay period between the end of bevacizumab treatment and surgery [51], and the fact that response to cetuximab, like panitumumab [52], is limited to those patients with tumors with wild-type KRAS mutation status [53-55].

Furthermore, in a phase III study, the combination of three cytotoxics, FOLFOXIRI, significantly increased response rate, radical surgical resection of metastases (6% versus 15% R0 all patients, P=0.033; 12% versus 36% R0 liver metastases-only patients, P=0.017), PFS and OS compared with FOLFIRI [37, 38]. Indeed, in a small single-arm French study (34 patients), 82% of patients achieved an R0 resection and the rate of complete clinical remission after surgery was 79% with a 2-year survival of 83% following triple cytotoxic drug therapy [56].

Evidence suggests that no chemotherapy backbone is preferred over another in combination with targeted agents. Cetuximab appears to be equally effective in combination with both irinotecan- and oxaliplatin-based combinations [57-59], and the evidence for bevacizumab is similar [23,60-62]. The phase III CALGB CALGB Cancer and Leukemia Group B  80405 trial in which patients are randomized to FOLFIRI/FOLFOX plus cetuximab or bevacizumab or cetuximab and bevacizumab [63] will hopefully answer this question and establish which targeted agent is the preferred combination partner. The primary end point is OS and the secondary end points include response, PFS, toxicity and resection rate. The targeted agents bevacizumab and cetuximab are also being combined with triple cytotoxic drug therapy [64-66]. The combination FOLFOXIRI plus cetuximab achieved a response rate of 85% and a resection rate of 75% [66]. More recent data from the small Italian phase II trial, presented at the American Society of Clinical Oncology American Society of Clinical Oncology, or ASCO, is an organization that represents all clinical oncologists. Every year, ASCO holds a large symposium where physicians and researchers meet to convey and discuss research and ideas.  (ASCO ASCO American Society of Clinical Oncology
ASCO Association of Schools and Colleges of Optometry (since 1941; Rockville, Maryland)
ASCO Australian Standard Classification of Occupations
ASCO Automatic Switch Company
) Annual Meeting 2008, showed the three-cytotoxic drug combination FOLFOXIRI plus bevacizumab to achieve an ORR of 75% and a disease control rate of 100% [67]. There may also be a place for new targeted agents in this clinical setting and sunitinib, an oral, multitargeted tyrosine kinase inhibitor Noun 1. tyrosine kinase inhibitor - a drug used in cases of chronic myeloid leukemia
medicament, medication, medicinal drug, medicine - (medicine) something that treats or prevents or alleviates the symptoms of disease
 that targets VEGF receptor and platelet-derived growth factor receptor The platelet-derived growth factors PDGF-A and -B have for already more than 30 years been recognized as important factors regulating cell proliferation, cellular differentiation, cell growth, development and many diseases including cancer.  (PDGFR PDGFR Platelet Derived Growth Factor Receptor ) produces liver tumor Hepatic tumors are tumors or growths on or in the liver (medical terms pertaining to the liver often start in hepato- or hepatic from the Greek word for liver, hepar). These growths can be benign or malignant (cancerous).  regression in the first-line setting in combination with FOLFIRI [68].

Significantly, we do not know for certain that resectability reflects long-term prognosis. The efficacy of a regimen may primarily be related to its ability to induce sufficient tumor regression to permit R0 resection, but probably what matters most is that the occult tumor cells that the surgeon cannot remove are killed, resulting in a long, relapse-free survival (RFS (Remote File System) A distributed file system for Unix computers introduced by AT&T in 1986 with Unix System V Release 3.0. It is similar to Sun's NFS, but only for Unix systems. ) after resection. The main concern in the neo-adjuvant setting for the treatment of CRC liver metastases is that we have no evidence for the impact the different regimens have on recurrence rates after resection. Disappointingly, for the majority of the patients who undergo hepatic resection secondary to neo-adjuvant chemotherapy, their disease will recur. Although the intent can properly be termed 'curative', cure is rarely achieved. Thus, new trials need to be conducted that link R0 resection to survival and investigate the precise roles of preoperative and postoperative chemotherapy with new trial end points, particularly RFS after surgery, that can provide a better measure of the efficacy of the different treatment regimens.

Resectable colorectal liver metastases

Today, chemotherapy before surgery, even in patients with resectable metastases, can increase the complete resection rate, facilitate limited hepatectomies, improve postoperative recovery, treat micrometastases, provide a test of chemoresponsiveness, identify aggressive disease, spare ineffective therapy and prolong RFS. This is supported by the results of the EORTC 40983 study where the PFS rate at 3 years was increased by 8.1% [hazard ratio The hazard ratio in survival analysis is the effect of an explanatory variable on the hazard or risk of an event. For a less technical definition than is provided here, consider hazard ratio to be an estimate of relative risk and see the explanation on that page.  (HR)=0.77; P=0.041] in those patients who received perioperative perioperative /peri·op·er·a·tive/ (-op´er-ah-tiv) pertaining to the period extending from the time of hospitalization for surgery to the time of discharge.

 chemotherapy and 9.2% (HR=0.73; P=0.025) in those patients who received perioperative chemotherapy when compared with surgery alone in the actually resected group of patients. Furthermore, single-center, nonrandomized studies with XELOX/FOLFOX [69] and XELOX plus bevacizumab [20] support the use of neo-adjuvant protocols for resectable metastases. At this time, the use of radiofrequency ablation Radiofrequency ablation (RFA)
A technique for removing a tumor by heating it with a radiofrequency current passed through a needle electrode.

Mentioned in: Liver Cancer, Prenatal Surgery
 cannot be recommended to replace surgical resection except in patients with comorbidities that prevent them from undergoing surgery, but it can be combined with resection to allow complete eradication of disease in the liver [70-72].

Time for a new treatment strategy?

Today, patients with metastatic CRC should be treated by multidisciplinary teams comprising surgeons, medical oncologists and radiologists. Evidence of the benefit of perioperative chemotherapy over surgery alone [10] and the potential benefit of adjuvant chemotherapy (after liver resection) [30] caused a rethink among the experts particularly in terms of the timing of the administration of chemotherapy for CRC patients with initially resectable liver and lung metastases lung metastases Oncology Cancer that has spread from the original–primary tumor to the lung; primary lung cancer spreads to the brain, bone, BM, liver. See Metastasis. .

Poor prognostic factors for patients with liver metastases are multiple metastases, >5 cm in diameter, synchronous presentation, lymph node-positive primary and high tumor marker tumor marker
A substance, released into the circulation by tumor tissue, whose detection in the serum indicates the presence of a specific type of tumor.
 levels [73]. Thus, even if the metastases were technically resectable (in terms of number, location and size), the panel considered that if the patient had more than one of the poor prognostic factors listed above, they should be referred for neo-adjuvant chemotherapy before surgery. The data from the EORTC study showed quite clearly that nearly all patients were able to tolerate neo-adjuvant chemotherapy. Also, analysis of the PFS curves from the EORTC-EPOC trial shows that the main difference comes after the first 2 months when the curves drop down and then move out in parallel, suggesting that the benefit conferred by perioperative chemotherapy might be a consequence of a reduction in the occurrence of early cancer relapse as a consequence of preoperative chemotherapy. The consensus from the panel was therefore that patients with, for example, a 2-cm solitary metastasis could go straight to surgery, with the recognition that this accounts for <10% of patients seen in routine clinical practice. All other patients with resectable metastases should be treated up front with chemotherapy, with the caveats that the patient is able to receive chemotherapy and the position of the lesion is not going to be lost. The panel also recommended that all resected patients should, if possible, receive postoperative adjuvant chemotherapy based on the data for the resected patients in the EORTC-EPOC trial [10]. In the case of those patients failing to respond, a multidisciplinary team discussion must decide whether it will be in the interests of the patient to change the chemotherapy regimen or to resect resect /re·sect/ (-sekt´) to excise part or all of an organ or other structure.

To perform a resection on a part of the body.
 their metastatic disease before it becomes unresectable. Fortunately, this situation is rare under modern treatment conditions with only 10%-15% of patients failing first-line chemotherapy. In the future, it is hoped that selection of the systemic therapy systemic therapy Therapeutics Any therapy that reaches target tissues via the systemic circulation  regimen, based on biological predictive factors, such as KRAS mutation status, will help to optimize the choice of first-line treatment A first-line treatment or first-line therapy is a medical therapy recommended for the initial treatment of a disease, sign or symptom, usually on the basis of empirical evidence for its efficacy.  and decrease the risk of immediate disease progression. It may also help direct second-line 'rescue' treatment strategies with the possibility of resection [63]. However, since surgery is still the only treatment modality treatment modality Medtalk The method used to treat a Pt for a particular condition  that has curative potential on its own, this may appear the most attractive approach in some situations, even if resistance to medical treatment generally means unfavorable tumor biology. The situation is much simpler in the case of those patients whose metastases were initially classified as unresectable, and systemic therapy should be administered until an adequate response has been achieved.



The panel concluded that true resectability rates are impossible to come by even from randomized trials. In specialist, centers for liver surgery patients will be directed toward multimodality management including surgery wherever possible but unfortunately this still may not always be the case outside these centers. Also, although the panel agreed that resectability was not a good end point for a clinical trial because it is too subjective, for the patient it is a very relevant end point. The word 'cure' has changed our approach to patients with liver metastases (Figure 1). In an ideal world, the aim of treatment would be to achieve good tumor shrinkage which enables surgery; but to capture all the permutations in a clinical trial setting is a major challenge. There is a clear need to distinguish between clinical trials and clinical practice and between agents that induce tumor shrinkage and those that just 'hold' the tumor. After ASCO 2008, there is a growing opinion that FOLFIRI or FOLFOX/XELOX plus cetuximab could be a valuable first-line therapy option for patients with wild-type KRAS tumors, with the same chemotherapy backbone plus bevacizumab for unselected patients or those patients with mutant KRAS.

The problem is that the issue of whether the targeted agents control micrometastases remains unresolved. Hopefully, the adjuvant trials (NSABP NSABP National Surgical Adjuvant Breast Project Oncology A series of ongoing multicenter clinical trials evaluating the effects of various therapies, including RT, surgery and chemotherapy–eg, tamoxifen and 5-FU, in treating advanced breast or colorectal CAs  C-08, AVANT and PETACC 8) will provide the data going forward. However, the consensus of the panel was that:

(i) Most patients, i.e. those with both with resectable and unresectable liver metastases (~90% of patients), should be treated up front with chemotherapy (Figure 1).

(ii) Perioperative chemotherapy is the way forward based on the data from the EORTC-EPOC trial.

(iii) However, patients with a 2-cm solitary metastasis and good prognostic features can probably go straight to surgery, particularly if there is a risk that the metastasis may disappear after chemotherapy, making resection of the involved part of the liver more difficult.

(iv) Most patients should if possible receive adjuvant chemotherapy after liver resection.

(v) However, with regard to the timing of the administration of chemotherapy, the total duration probably should be limited to a maximum of 6 months to include both pre- and postoperative chemotherapy.

(vi) There is an urgent need to look at the long-term advantages of chemotherapy and targeted agents in terms of RFS after resection.

(vii) A new clinically important end point is DFS at a certain time point e.g.: 6- and 12-month post-liver resection (or 12- to 18-month post-treatment start) and should be discussed as an end point in trials where the liver tumor burden is properly defined.

(viii) In the future due to KRAS data linked to EGFR EGFR Epidermal Growth Factor Receptor (a kinase enzyme)
EGFR Estimated Glomerular Filtration Rate
 inhibitors, patient populations will have to be selected wherever possible.

(ix) Studies with new targeted agents should be investigated second line in the first instance in BOND2-like trials to establish efficacy.

Finally, the panel recommended that the multidisciplinary teams that are involved in the management of these patients must always balance what is technically feasible and biologically sound (with respect to the tumor) against potential patient benefit.


The workshop was supported by Pfizer Oncology.


Pfizer exerted no influence on either the outcome of the meeting or the content of this manuscript. Editorial support was provided by Cancer Communications and Consultancy Ltd. Other members of the European Colorectal Metastases Treatment Group present at the meeting: Alfredo Carrato MD, PhD, Elche University Hospital, Alicante, Spain; Jy-Ming Chiang MD, Chang Gung Memorial Hospital, Taiwan; Bernard De Hemptinne MD, University Hospital Ghent, Belgium; Alfredo Falcone MD, Department of Oncology, Azienda USL-6 of Livorno Italy; Joan Figueras MD, Hospital Trueta, Girona, Spain; Jean-Francois Gigot MD, Saint-Luc University Hospital, Brussels, Belgium; Vassilis Georgoulias, Heraklion University Hospital, Crete; Felice Giuliante MD, Universita Cattolica del Sacro Cuore, Rome, Italy; Rob Glynne-Jones MD, Mount Vernon Mount Vernon, estate, United States
Mount Vernon, NE Va., overlooking the Potomac River near Alexandria, S of Washington, D.C.; home of George Washington from 1747 until his death in 1799.
 Cancer Centre, Middlesex, UK; Claus-Henning Kohne, Klinik fur Innere Medizin ll, Oldenburg, Germany; Dimitris Papamichael Dimitris Papamichael (Greek: Δημήτρης Παπαμιχαήλ, born 1934 in Athens; died 8 August, 2004 in Athens 12pm at his house,) was a famous Greek actor and director.  MB BS FRCP FRCP Fellow of the Royal College of Physicians.

Fellow of the Royal College of Physicians
, Bank of Cyprus Bank of Cyprus (CSE: BOCY ATHEX: BOC ), is a major Cypriot financial institution. History
The company started off as "The Nicosia Depository" («Ταμιευτήριο η
 Oncology Center, Nicosia, Cyprus; Graeme Poston MD, University Hospital Aintree, Liverpool, UK; Carmelo Pozzo MD, Universita Cattolica del Sacro Cuore, Rome, Italy; Josep Tabernero MD, Vall d'Hebron University Hospital, Barcelona, Spain; Harpreet Wasan MD, Hammersmith Hospital Hammersmith Hospital is a major teaching hospital in West London. It is associated with the Imperial College medical faculty and is part of the Imperial College Healthcare NHS Trust in the London Borough of Hammersmith and Fulham.  Campus, London, UK; Richard Wilson MD, Queen's University Belfast Queen's University Belfast (Irish: Ollscoil na Banríona, Béal Feirste) is a university in Belfast, Northern Ireland and a member of the Russell Group (a lobby group of major research universities in the United Kingdom). , Belfast, UK.

doi:10.1093/annonc/mdn735 I 3


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Reprinted with kind permission of Annals of Oncology

Correspondence to: Philippe Rougier

Department of Hepato-Gastroenterology

Ambroise Pare Hospital

9 Avenue Charles de Gaulle

92100 Boulogne-Billancourt

Paris, France


Bernard Nordlinger (1) ([dagger]), Eric Van Cutsem (2) ([dagger]), Thomas Gruenberger (3), Bengt Glimelius (4,5), Graeme Poston (6), Philippe Rougier1, Alberto Sobrero (7) and Marc Ychou (8)

on behalf of the European Colorectal Metastases Treatment Group

(1) Department of Digestive Surgery, Ambroise Pare Hospital, Boulogne, France; (2) Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven, Belgium; (3) Department of General Surgery, University of Vienna History
The University was founded on March 12, 1365 by Duke Rudolph IV and his brothers Albert III and Leopold III, hence the additional name "Alma Mater Rudolphina". After the Charles University in Prague, the University of Vienna is the second oldest university in Central
, Vienna, Austria; (4) Department of Oncology, Radiology and Clinical Immunology, University of Uppsala, Uppsala; (5) Department of Oncology and Pathology, Karolinska Institute, Stockholm, Sweden; (6) Department of Surgery, University Hospital Aintree, Liverpool, UK; (7) Medical Oncology, San Martino Hospital, Genova, Italy; (8) CRLC CRLC Capitol Region Library Council (Connecticut)
CRLC Central Region Leadership Conference (DECA) 
 Val d'Aurelle, Montpellier Cedex 05, France ([dagger]) Both authors contributed equally.
Table 1: Adjuvant therapy after R0 resection: joint analysis of the
FFCD 9002 and EORTC/NCIC CTG/GIVIO trials [31]

                                Progression-free survival
                          Surgery+ chemotherapy    Surgery alone

Number of patients (a)             137                  137
Median (months)             27.9 (21.0-41.9)      18.8 (14.7-23.8)
Hazard ratio                1.32 (1.00-1.76)
P (log-rank test)                 0.058

                                     Overall survival
                          Surgery+ chemotherapy    Surgery alone

Number of patients (a)             137                  137
Median (months)              62.2 (45.2-NR)       47.3 (40.6-57.2)
Hazard ratio                1.32 (0.95-1.82)
P (log-rank test)                 0.095

(a) Four patients from ENG trial excluded from survival analysis
because the date of metastases resection is missing. NR, not reached.

Table 2: Efficacy end points from randomized studies for first-line

                            CRYSTAL FOLFIRI        OPUS FOLFOX
                                [+ or -]            [+ or -]
                           cetuximab [45, 46]   cetuximab [44, 47]

ORR in TIT, %                 39 versus 47         36 versus 46
P value                          0.004                 0.64
ORR in KRAS wild type, %      43 versus 59         37 versus 61
P value                          0.0025                0.01
R0 resection rate, %         1.5 versus 4.3       2.4 versus 4.7
P value (odds ratio)         0.003 3 (3.0)              NS
PFS months                   8.0 versus 8.9       7.2 versus 7.2
P value (hazards ratio)       0.048 (0.85)         0.62 (0.93)

KRAS wild type, patients whose tumors harbor no mutations at codons 12
and 13 of the KRAS gene.

ORR, overall response rate; ITT, intention to treat; NS, not
significant; PFS, progression-free survival.
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Title Annotation:Feature Article
Author:Nordlinger, Bernard; Van Cutsem, Eric; Gruenberger, Thomas; Glimelius, Bengt; Poston, Graeme; Rougie
Publication:Advances in Gastrointestinal Cancer
Article Type:Reprint
Geographic Code:4EUFR
Date:Jun 1, 2009
Previous Article:American Society of Clinical Oncology (ASCO).
Next Article:Evolution of multidisciplinary care for patients with metastatic colorectal cancer: the 'win-win' combination of surgery and chemotherapy.

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Evolution of multidisciplinary care for patients with metastatic colorectal cancer: the 'win-win' combination of surgery and chemotherapy.
The future is BRiTE.
15th Congress of the European Cancer Organization and the 34th European Society for Medical Oncology multidisciplinary congress: GI update.

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