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    R1 Resection by Necessity for Colorectal Liver MetastasesIs It Still a Contraindication to Surgery?

    Robbert J. de Haas, MD,* Dennis A. Wicherts, MD,* Eduardo Flores, MD,*Daniel Azoulay, MD, PhD,* Denis Castaing, MD,* and Rene Adam, MD, PhD*

    Objective: To compare long-term outcome of R0 (negative margins)and R1 (positive margins) liver resections for colorectal liver metastases(CLM) treated by an aggressive approach combining chemotherapy andrepeat surgery.Summary Background Data: Complete macroscopic resection withnegative margins is the gold standard recommendation in the surgicaltreatment of CLM. However, due to vascular proximity or multinodu-larity, complete macroscopic resection can sometimes only be per-formed through R1 resection. Increasingly efficient chemotherapy mayhave changed long-term outcome after R1 resection.Methods: All resected CLM patients (R0 or R1) at our institution between1990 and 2006 were prospectively evaluated. Exclusion criteria were:macroscopic incomplete (R2) resection, use of local treatment modalities,and presence of extrahepatic disease. We aimed to resect all identifiedmetastases with negative margins. However, when safe margins could notbe obtained, resection was still performed provided complete macroscopictumor removal. Overall survival (OS) and disease-free survival werecompared between groups, and prognostic factors were identified.Results: Of 840 patients, 436 (52%) were eligible for the study, 234(28%) of whom underwent R0 resection, and 202 (24%) underwent R1resection. Number and size of CLM were higher, and distribution wasmore often bilateral in the R1 group. After a mean follow-up of 40months, 5-year OS was 61% and 57% for R0 and R1 patients (P 0.27). Five-year disease-free survival was 29% in the R0 group versus20% in the R1 group (P 0.12). In the R1 group, intrahepatic (but notsurgical margin) recurrences were more often observed (28% vs. 17%; P 0.004). Preoperative carcinoembryonic antigen level 10 ng/mL andmajor hepatectomy, but not R1 resection, were independent predictors ofpoor OS. Size 30 mm, bilateral distribution, and intraoperative bloodtransfusions independently predicted positive surgical margins.Conclusions: Despite a higher recurrence rate, the contraindicationof R1 resection should be revisited in the current era of effectivechemotherapy because survival is similar to that of R0 resection.

    (Ann Surg 2008;248: 626637)

    Liver resection is still the only chance of cure for patientswith colorectal metastases, resulting in 5-year survival rates upto 67% for highly selected patients.1 Unfortunately, at the time ofdiagnosis, only one-fifth of patients with colorectal liver metastases(CLM) presents with resectable lesions.2 Nowadays, an importantamount of patients initially considered as having unresectable CLMcan be converted to resectability by the aid of modern chemother-apy regimens consisting of 5-fluorouracil, leucovorin, oxaliplatin,and/or irinotecan.36 In addition, chemotherapy efficacy can befurther increased by the use of monoclonal antibodies like cetux-imab and bevacizumab.79 Besides this, surgical improvements likeportal vein embolization, which allows hypertrophy of a smallremnant liver volume, and vascular resection and reconstructiontechniques enable hepatic resection in an additional number ofpatients.10,11 However, due to the increased number of patients withmultinodular disease and/or CLM close to important vascular struc-tures, macroscopic complete resection of all CLM can sometimesonly be performed with positive surgical margins.

    Within the literature, the inability to achieve clearresection margins is generally considered as contraindicationto surgery because it has been associated with significantlyreduced survival rates,1220 and an increased risk of surgicalmargin recurrence.16,21 Several cutoff points for the optimalnegative resection margin width have been proposed, varyingbetween 2 and 10 mm;2228 however, complete macroscopicremoval of all lesions with negative resection margins, irre-spective of the width, is currently the gold standard recom-mendation in the surgical treatment of CLM.

    At our institute, the inability to obtain a free surgicalmargin during liver resection for CLM has never been con-sidered a contraindication to surgery, provided completemacroscopic removal of all metastatic lesions. As increas-ingly effective chemotherapy regimens might have changedthe spectrum of this particular situation, we compared long-term outcome in patients with microscopically positive andnegative resection margins who were all treated by an ag-gressive approach consisting of chemotherapy and repeatsurgery to assess the validity of this policy.


    Study PopulationAll consecutive patients treated by hepatic resection for CLM

    at our hospital between January 1990 and January 2006, and whofulfilled the following criteria were eligible for the study: (1)macroscopic complete resection; (2) clear description of surgical

    From the *AP-HP Hopital Paul Brousse, Centre Hepato-Biliaire, Villejuif,France; Department of Surgery, University Medical Center Utrecht,Utrecht, The Netherlands; Universite Paris-Sud, Villejuif, France; andthe Inserm, Villejuif, France.

    Reprints: Rene Adam, MD, PhD, AP-HP Hopital Paul Brousse, CentreHepato-Biliaire, 12 Avenue Paul Vaillant Couturier, 94804 Villejuif,France. E-mail: [email protected]

    Copyright 2008 by Lippincott Williams & WilkinsISSN: 0003-4932/08/24804-0626DOI: 10.1097/SLA.0b013e31818a07f1

    Annals of Surgery Volume 248, Number 4, October 2008626

  • margin status by the pathologist for each metastasis; (3) no evidenceof concomitant extrahepatic disease; (4) no simultaneous use oflocal treatment modalities (ie, radiofrequency ablation and/or cryo-surgery). Patients were selected from our prospectively maintainedinstitutional database, and each medical chart was reviewed.

    Preoperative EvaluationAll patients were preoperatively evaluated by thoracoab-

    dominal imaging (ultrasonography, computed tomography (CT)),routine blood tests, serum tumor marker levels (carcinoembryonicantigen (CEA) and/or CA19.9), and colonoscopy. Preoperativechemotherapy was administered when liver metastases were ini-tially unresectable (ie, inability to completely remove all CLM witha sufficient remnant liver volume), or in a neoadjuvant setting incase of synchronous (diagnosed before, during, or within 3 monthsafter colorectal resection) or in case of marginally resectable (5bilateral nodules) CLM. Chemotherapy response was monitoredevery 2 months by CT imaging, according to the World HealthOrganization guidelines29 or, more recently, by using theResponse Evaluation Criteria in Solid Tumors (RECIST).30 Ifthe estimated future remnant liver volume was still insuffi-cient after chemotherapy, portal vein embolization was per-formed to induce compensatory hypertrophy of the remainingliver.10

    Hepatic ResectionDuring laparotomy, thorough abdominal exploration was

    performed to rule out extrahepatic disease sites. Palpation of theliver and intraoperative ultrasound were carried out to confirm thenumber and size of the lesions, to define their relation with intra-hepatic vascular structures, and to search for occult CLM. Paren-chymal transection was performed using the ultrasonic dissector(Cavitron Ultrasonic Surgical Aspirator, Valleylab, Boulder, CO)and a fenestrated bipolar forceps. The goal of surgery was to resectall identified tumor deposits with a tumor-free margin. However,when a tumor-free resection margin could not be obtained, owing tovascular proximity or multinodularity, resection was still performedprovided that all metastatic lesions were macroscopically com-pletely removed. To prevent local recurrences in these cases, appli-cation of argon beam or bipolar coagulation was routinely per-formed on the cut section. Postoperatively, all resection specimenswere examined by conventional histopathological examination. Ac-

    cording to the guidelines of the International Union Against Cancer,R0 and R1 resections were defined by the absence (tumor-freemargin 1 mm for all detected lesions) or presence (tumor-free margin 0 mm) of microscopic tumor invasion of the resectionmargins, respectively.31 In case of microscopic tumor invasion, theadditional opinion of the operating surgeon with regard to thecomplete macroscopic resection of all lesions, differentiated R1from R2 resections.

    Postoperative Follow-UpRegular postoperative follow-up started at 1 month pos-

    thepatectomy, and then every 4 months, consisting of routineblood tests, serum tumor marker evaluation (CEA and/orCA19.9), and hepatic ultrasound. Thoracoabdominal CT imag-ing was performed every 8 months. After hepatectomy, patientswere treated by systemic chemotherapy to decrease the recur-rence risk. If an intrahepatic and/or extrahepatic recurrenceoccurred, repeat surgery was performed if potentially curative.32

    Statistical AnalysisTo assess the impact of R1 resections on long-term outcome,

    patients were divided according to their surgical margin status intoa R0 group and a R1 group. 2 test was used to compare categoricaldata, and continuous data were compared using the independent-samples t test. Survival time was calculated from the date of hepaticresection until death or last follow-up. Progression-free survival(PFS) was defined as the time-interval between hepatectomy andfirst postoperative recurrence or death, whereas disease-free sur-vival (DFS) was defined as the time-interval between the hepatec-tomy and either the first recurrence that could not be curativelytreated (resection or ablation) or death. Survival curves were gen-erated by the Kaplan-Meier method, and were compared by thelog-rank test. To identify predictors of survival, univariate andmultivariate analyses were performed, using