Evelyne M. Loyer

Effect of Surgical Margin Status on Survival and Site of Recurrence After Hepatic Resection for Colorectal Metastases

Objective:To evaluate the influence of surgical margin status on survival and site of recurrence in patients treated with hepatic resection for colorectal metastases. Methods:Using a multicenter database, 557 patients who underwent hepatic resection for colorectal metastases were identified. Demographics, operative data, pathologic margin status, site of recurrence (margin, other intrahepatic site, extrahepatic), and long-term survival data were collected and analyzed. Results:On final pathologic analysis, margin status was positive in 45 patients, and negative by 1 to 4 mm in 129, 5 to 9 mm in 85, and ≥1 cm in 298. At a median follow-up of 29 months, the 1-, 3-, and 5-year actuarial survival rates were 97%, 74%, and 58%; median survival was 74 months. Tumor size ≥5 cm, >3 tumor nodules, and carcinoembryonic antigen level >200 ng/mL predicted poor survival (all P < 0.05). Median survival was 49 months in patients with positive margins and not yet reached in patients with negative margins (P = 0.01). After hepatic resection, 225 (40.4%) patients had recurrence: 21 at the surgical margin, 56 at another intrahepatic site, 82 at an extrahepatic site, and 66 at both intrahepatic and extrahepatic sites. Patients with negative margins of 1 to 4 mm, 5 to 9 mm, and ≥1 cm had similar overall recurrence rates (P > 0.05). Patients with positive margins were more likely to have surgical margin recurrence (P = 0.003). Adverse preoperative biologic factors including tumor number greater than 3 (P = 0.01) and a preoperative CEA level greater than 200 ng/mL (P = 0.04) were associated with an increased risk of positive surgical margin. Conclusions:A positive margin after resection of hepatic colorectal metastases is associated with adverse biologic factors and increased risk of surgical-margin recurrence. The width of a negative surgical margin does not affect survival, recurrence risk, or site of recurrence. A predicted margin of <1 cm after resection of hepatic colorectal metastases should not be used as an exclusion criterion for resection.

Portal vein embolization before major hepatectomy and its effects on regeneration, resectability and outcome

This study evaluated the safety of portal vein embolization (PVE), its impact on future liver remnant (FLR) volume and regeneration, and subsequent effects on outcome after liver resection.

Early and late complications after radiofrequency ablation of malignant liver tumors in 608 patients

Background:Radiofrequency ablation (RFA) has become a common treatment of patients with unresectable primary and secondary hepatic malignancies. We performed this prospective analysis to determine early (within 30 days) and late (more than 30 days after) complication rates associated with hepatic tumor RFA. Methods:All patients treated between January 1, 1996 and June 30, 2002 with RFA for hepatic malignancies were entered into a prospective database. Patients were evaluated during RFA treatment, throughout the immediate post RFA course, and then every 3 months after RFA to assess for the development of treatment-related complications. Results:A total of 608 patients, 345 men (56.7%) and 263 women (43.3%), with a median age of 58 years (range 18–85 years) underwent RFA of 1225 malignant liver tumors. Open intraoperative RFA was performed in 382 patients (62.8%), while percutaneous RFA was performed in 226 (37.2%). The treatment-related mortality rate was 0.5%. Early complications developed in 43 patients (7.1%). Early complications were more likely to occur in patients treated with open RFA (33 [8.6%] of 382 patients) compared with percutaneous RFA (10 [4.4%] 226 patients, P < 0.01), and in patients with cirrhosis (25 [12.9%] complications in 194 patients) compared with noncirrhotic patients (31 [7.5%] complications in 414 patients, P < 0.05). Late complications arose in 15 patients (2.4%) with no difference in incidence between open and percutaneous RFA treatment. The combined overall early and late complication rate was 9.5%. Conclusions:Hepatic tumor RFA can be performed with low mortality and morbidity rates. Though relatively rare, late complications can develop and physicians performing hepatic RFA must be cognizant of these delayed treatment-related problems.

Association of computed tomography morphologic criteria with pathologic response and survival in patients treated with bevacizumab for colorectal liver metastases.

CONTEXT The standard criteria used to evaluate tumor response, the Response Evaluation Criteria in Solid Tumors (RECIST), were developed to assess tumor shrinkage after cytotoxic chemotherapy and may be limited in assessing response to biologic agents, which have a cytostatic mechanism of action. OBJECTIVE To validate novel tumor response criteria based on morphologic changes observed on computed tomography (CT) in patients with colorectal liver metastases treated with bevacizumab-containing chemotherapy regimens. DESIGN, SETTING, AND PATIENTS A total of 234 colorectal liver metastases were analyzed from 50 patients who underwent hepatic resection after preoperative chemotherapy that included bevacizumab at a comprehensive US cancer center from 2004 to 2007; date of last follow-up was March 2008. All patients underwent routine contrast-enhanced CT at the start and end of preoperative therapy. Three blinded, independent radiologists evaluated images for morphologic response, based on metastases changing from heterogeneous masses with ill-defined margins into homogeneous hypoattenuating lesions with sharp borders. These criteria were validated with a separate cohort of 82 patients with unresectable colorectal liver metastases treated with bevacizumab-containing chemotherapy. MAIN OUTCOME MEASURES Response determined using morphologic criteria and RECIST was correlated with pathologic response in resected liver specimens and with patient survival. RESULTS Interobserver agreement for scoring morphologic changes was good among 3 radiologists (kappa, 0.68-0.78; 95% confidence interval [CI], 0.51-0.93). In resected tumor specimens, the median (interquartile range [IQR]) percentages of residual tumor cells for optimal morphologic response was 20% (10%-30%); for incomplete response, 50% (30%-60%); and no response, 70% (60%-70%; P < .001). With RECIST, the median (IQR) percentages of residual tumor cells were for partial response 30% (10%-60%); for stable disease, 50% (20%-70%); and for progressive disease, 70% (65%-70%; P = .04). Among patients who underwent hepatic resection, median overall survival was not yet reached with optimal morphologic response and 25 months (95% CI, 20.2-29.8 months) with incomplete or no morphologic response (P = .03). In the validation cohort, patients with optimal morphologic response had median overall survival of 31 months (95% CI, 26.8-35.2 months) compared with 19 months (95% CI, 14.6-23.4 months) with incomplete or no morphologic response (P = .009). RECIST did not correlate with survival in either the surgical or validation cohort. CONCLUSION Among patients with colorectal liver metastases treated with bevacizumab-containing chemotherapy, CT-based morphologic criteria had a statistically significant association with pathologic response and overall survival.

High Survival Rate After Two-Stage Resection of Advanced Colorectal Liver Metastases: Response-Based Selection and Complete Resection Define Outcome

PURPOSE Prolonged survival after two-stage resection (TSR) of advanced colorectal liver metastases (CLM) may be the result of selection of best responders to chemotherapy. The impact of complete resection in this well-selected group is controversial. PATIENTS AND METHODS Data on 890 patients undergoing resection and 879 patients who received only chemotherapy for CLM were collected prospectively. We used intent-to-treat analysis to evaluate the survival of patients who underwent TSR. Additionally, we evaluated a cohort of nonsurgically treated patients selected to mirror the TSR population: colorectal metastases with liver-only disease, objective response to chemotherapy, and alive 1 year after chemotherapy initiation. RESULTS Sixty-five patients underwent the first stage of TSR; 62 patients fulfilled the inclusion criteria for the medical group. TSR patients had a mean of 6.7 ± 3.4 CLM with mean size of 4.5 ± 3.1 cm. Nonsurgical patients had a mean of 5.9 ± 2.9 CLM with mean size of 5.4 ± 3.4 cm (not significant). Forty-seven TSR patients (72%) completed the second stage. Progression between stages was the main cause of noncompletion of the second stage (61%). After 50 months median follow-up, the 5-year survival rate was 51% in the TSR group and 15% in the medical group (P = .005). In patients who underwent TSR, noncompletion of TSR and major postoperative complications were independently associated with worse survival. CONCLUSION TSR is associated with excellent outcome in patients with advanced CLM as a result of both selection by chemotherapy and complete resection of metastatic disease.

The oncosurgery approach to managing liver metastases from colorectal cancer: a multidisciplinary international consensus

An international panel of multidisciplinary experts convened to develop recommendations for the management of patients with liver metastases from colorectal cancer (CRC). The aim was to address the main issues facing the CRC hepatobiliary multidisciplinary team (MDT) when managing such patients and to standardize the treatment patients receive in different centers. Based on current evidence, the group agreed on a number of issues including the following: (a) the primary aim of treatment is achieving a long disease-free survival (DFS) interval following resection; (b) assessment of resectability should be performed with high-quality cross-sectional imaging, staging the liver with magnetic resonance imaging and/or abdominal computed tomography (CT), depending on local expertise, staging extrahepatic disease with thoracic and pelvic CT, and, in selected cases, fluorodeoxyglucose positron emission tomography with ultrasound (preferably contrast-enhanced ultrasound) for intraoperative staging; (c) optimal first-line chemotherapy-doublet or triplet chemotherapy regimens combined with targeted therapy-is advisable in potentially resectable patients; (d) in this situation, at least four courses of first-line chemotherapy should be given, with assessment of tumor response every 2 months; (e) response assessed by the Response Evaluation Criteria in Solid Tumors (conventional chemotherapy) or nonsize-based morphological changes (antiangiogenic agents) is clearly correlated with outcome; no imaging technique is currently able to accurately diagnose complete pathological response but high-quality imaging is crucial for patient management; (f) the duration of chemotherapy should be as short as possible and resection achieved as soon as technically possible in the absence of tumor progression; (g) the number of metastases or patient age should not be an absolute contraindication to surgery combined with chemotherapy; (h) for synchronous metastases, it is not advisable to undertake major hepatic surgery during surgery for removal of the primary CRC; the reverse surgical approach (liver first) produces as good an outcome as the conventional approach in selected cases; (i) for patients with resectable liver metastases from CRC, perioperative chemotherapy may be associated with a modestly better DFS outcome; and (j) whether initially resectable or unresectable, cure or at least a long survival duration is possible after complete resection of the metastases, and MDT treatment is essential for improving clinical and survival outcomes. The group proposed a new system to classify initial unresectability based on technical and oncological contraindications.

Selection for hepatic resection of colorectal liver metastases: expert consensus statement

Hepatic resection offers a chance of a cure in selected patients with colorectal liver metastases (CLM). To achieve adequate patient selection and curative surgery, (i) precise assessment of the extent of disease, (ii) sensitive criteria for chemotherapy effect, (iii) adequate decision making in surgical indication and (iv) an optimal surgical approach for pre-treated tumours are required. For assessment of the extent of the disease, contrast-enhanced computed tomography (CT) and/or magnetic resonance imaging (MRI) with gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) is recommended depending on the local expertise and availability. Positron emission tomography (PET) and PET/CT may offer additive information in detecting extrahepatic disease. The RECIST criteria are a reasonable method to evaluate the effect of chemotherapy. However, they are imperfect in predicting a pathological response in the era of modern systemic therapy with biological agents. The assessment of radiographical morphological changes is a better surrogate of the pathological response and survival especially in the patients treated with bevacizumab. Resectability of CLM is dependent on both anatomic and oncological factors. To decrease the surgical risk, a sufficient volume of liver remnant with adequate blood perfusion and biliary drainage is required according to the degree of histopathological injury of the underlying liver. Portal vein embolization is sometimes required to decrease the surgical risk in a patient with small future liver remnant volume. As a complete radiological response does not signify a complete pathological response, liver resection should include all the site of a tumour detected prior to systemic treatment.

Vascular involvement in pancreatic adenocarcinoma:reassessment by thin-section CT

Abstract. We defined computed tomographic (CT) criteria of vascular involvement by pancreatic carcinoma and used these criteria to assess vascular involvement in 56 patients with pancreatic adenocarcinoma. CT of the pancreas was performed at 1.5-mm section thickness and 5-mm section intervals during a bolus phase of intravenous contrast enhancement. The type of vascular involvement was correlated with surgical and pathologic findings. When there was fat-plane (type A) or normal pancreatic parenchyma (type B) separating the tumor from adjacent vessels, the tumor could be resected without venous resection in 21 of 22 patients (95%). When the tumor was inseparable from the vessels but the points of contact formed a convexity against the vessel (type C), CT was not reliable in predicting whether or not the tumor was fixed against the vessel. When the tumor was partially encircling (type D) the vessel, the tumor was fixed against the vessels in most cases. The resectable rate was 47%, but resection would also require venous resection. When the tumor was completely encircling (type E) or occluding (type F<+>) the vessel, all tumors were not resectable with a negative margin. Thin-section CT with bolus intravenous contrast enhancement improved the ability to assess vascular involvement in pancreatic adenocarcinoma.

Clinical evaluation of the delivery and safety of aerosolized liposomal 9-nitro-20(S)-camptothecin in patients with advanced pulmonary malignancies

Purpose: The purpose is to evaluate the feasibility and safety of aerosol administration of the topoisomerase I inhibitor, 9-nitrocamptothecin, in a liposome formulation, and to recommend a dosage for a Phase II trial for an 8-week daily treatment schedule. Experimental Design: Patients with primary or metastatic lung cancer received aerosolized liposomal 9-nitrocamptothecin for 5 consecutive days/week for 1, 2, 4, or 6 weeks followed by 2 weeks of rest to determine feasibility. For the Phase I part, the dose was increased stepwise from 6.7 up to 26.6 μg/kg/day Monday to Friday for 8 weeks followed by 2 weeks of rest. Results: Twenty-five patients received treatment. The mean baseline forced expiratory volume in 1 second for all patients was 85% of predicted. A dose-limiting toxicity was chemical pharyngitis seen after 1 week in 2 of 2 patients at 26.6 μg/kg/day. At 20.0 μg/kg/day, grade 2 and 3 fatigue prompting a dose reduction was seen after 4 weeks in 2 of 4 patients. Grade 2 toxic effects included nausea/vomiting (9 patients), cough and bronchial irritation (6 patients), fatigue (5 patients), anemia (4 patients), neutropenia (2 patients), anorexia (1 patient), and skin rash around the face mask (1 patient). 9-Nitro-20(S)-camptothecin (9NC) was absorbed systemically. Partial remissions were observed in 2 patients with uterine cancer, and stabilization occurred in 3 patients with primary lung cancer. Conclusions: Aerosol administration of liposomal 9NC was found to be feasible and safe. 9NC delivered as an aerosol was detected in patient’s plasma shortly after the start of treatment. The recommended dose for Phase II studies is 13.3 μg/kg/day (equivalent to 0.5 mg/m2/day), which constitutes two consecutive 30-min nebulizations/day from a nebulizer reservoir with 4 mg of 9NC in 10 ml of sterile water, Monday to Friday for 8 weeks every 10 weeks.

Optimal Morphologic Response to Preoperative Chemotherapy: An Alternate Outcome End Point Before Resection of Hepatic Colorectal Metastases

PURPOSE The purposes of this study were to confirm the prognostic value of an optimal morphologic response to preoperative chemotherapy in patients undergoing chemotherapy with or without bevacizumab before resection of colorectal liver metastases (CLM) and to identify predictors of the optimal morphologic response. PATIENTS AND METHODS The study included 209 patients who underwent resection of CLM after preoperative chemotherapy with oxaliplatin- or irinotecan-based regimens with or without bevacizumab. Radiologic responses were classified as optimal or suboptimal according to the morphologic response criteria. Overall survival (OS) was determined, and prognostic factors associated with an optimal response were identified in multivariate analysis. RESULTS An optimal morphologic response was observed in 47% of patients treated with bevacizumab and 12% of patients treated without bevacizumab (P < .001). The 3- and 5-year OS rates were higher in the optimal response group (82% and 74%, respectively) compared with the suboptimal response group (60% and 45%, respectively; P < .001). On multivariate analysis, suboptimal morphologic response was an independent predictor of worse OS (hazard ratio, 2.09; P = .007). Receipt of bevacizumab (odds ratio, 6.71; P < .001) and largest metastasis before chemotherapy of ≤ 3 cm (odds ratio, 2.12; P = .025) were significantly associated with optimal morphologic response. The morphologic response showed no specific correlation with conventional size-based RECIST criteria, and it was superior to RECIST in predicting major pathologic response. CONCLUSION Independent of preoperative chemotherapy regimen, optimal morphologic response is sufficiently correlated with OS to be considered a surrogate therapeutic end point for patients with CLM.