Bernard Paule

Rescue Surgery for Unresectable Colorectal Liver Metastases Downstaged by Chemotherapy: A Model to Predict Long-term Survival

Objective:To evaluate the long-term survival of patients resected for primarily unresectable colorectal liver metastases (CRLM) downstaged by systemic chemotherapy and to use prognostic factors of outcome for a model predictive of survival on a preoperative setting. Summary Background Data:Surgery of primarily unresectable CRLM after downstaging chemotherapy is still questioned, and prognostic factors of outcome are lacking. Methods:From a consecutive series of 1439 patients with CRLM managed in a single institution during an 11-year period (1988–1999), 1104 (77%) initially unresectable (NR) patients were treated by chemotherapy and 335 (23%) resectable were treated by primary liver resection. Chemotherapy mainly consisted of 5-fluorouracil and leucovorin combined to oxaliplatin (70%), irinotecan (7%), or both (4%) given as chronomodulated infusion (87%). NR patients were routinely reassessed every 4 courses. Surgery was reconsidered every time a documented response to chemotherapy was observed. Among 1104 NR patients, 138 “good responders” (12.5%) underwent secondary hepatic resection after an average of 10 courses of chemotherapy. At time of diagnosis, mean number of metastases was 4.4 (1–14) and mean maximum size was 5.2 cm (1–25). Extrahepatic tumor was present in 52 patients (38%). Multinodularity or extrahepatic tumor was the main cause of initial unresectability. All factors likely to be predictive of survival after liver resection were evaluated by uni- and multivariate analysis. Estimation of survival was adjusted on risk factors available preoperatively. Results:Seventy-five percent of procedures were major hepatectomies (≥3 segments) and 93% were potentially curative. Liver surgery was combined to portal embolization, to ablative treatment, or to a second-stage hepatectomy in 42 patients (30%) and to resection of extrahepatic tumor in 41 patients (30%). Operative mortality within 2 months was 0.7%, and postoperative morbidity was 28%. After a mean follow-up of 48.7 months, 111 of the 138 patients (80%) developed tumor recurrence, 40 of which were hepatic (29%), 12 extrahepatic (9%), and 59 both hepatic and extrahepatic (43%). Recurrence was treated in 52 patients by repeat hepatectomy (71 procedures) and in 42 patients by extrahepatic resection (77 procedures). Survival was 33% and 23% at 5 and 10 years with a disease-free survival of 22% and 17%, respectively. It was decreased as compared with that of patients primarily resected within the same period (48% and 30% respectively, P = 0.01). At the last follow-up, 99 patients had died (72%) and 39 (28%) were alive; 25 were disease free (18%) and 14 had recurrence (10%). At multivariate analysis, 4 preoperative factors were independently associated to decreased survival: rectal primary, ≥3 metastases, maximum tumor size >10 cm, and CA 19–9 >100 UI/L. Mean adjusted 5-year survival according to the presence of 0, 1, 2, 3, or 4 factors was 59%, 30%, 7%, 0%, and 0%. Conclusions:Modern chemotherapy allows 12.5% of patients with unresectable CRLM to be rescued by liver surgery. Despite a high rate of recurrence, 5-year survival is 33% overall, with a wide use of repeat hepatectomies and extrahepatic resections. Four preoperative risk factors could select the patients most likely to benefit from this strategy.

Tumor Progression While on Chemotherapy: A Contraindication to Liver Resection for Multiple Colorectal Metastases?

Objective:To evaluate the influence of the response to preoperative chemotherapy, especially tumor progression, on the outcome following resection of multiple colorectal liver metastases (CRM). Summary Background Data:Hepatic resection is the only treatment that currently offers a chance of long-term survival, although it is associated with a poor outcome in patients with multinodular CRM. Because of its better efficacy, chemotherapy is increasingly proposed as neoadjuvant treatment in such patients to allow or to facilitate the radicality of resection. However, little is known of the efficacy of such a strategy and the influence of the response to chemotherapy on the outcome of hepatic resection. Methods:We retrospectively analyzed the course of 131 consecutive patients who underwent liver resection for multiple (≥4) CRM after systemic chemotherapy between 1993 and 2000, representing 30% of all liver resections performed for CRM in our institution during that period. Chemotherapy included mainly 5-fluorouracil, leucovorin, and either oxaliplatin or irinotecan for a mean of 9.8 courses (median, 9 courses). Patients were divided into 3 groups according to the type of response obtained to preoperative chemotherapy. All liver resections were performed with curative intent. We analyzed patient outcome in relation to response to preoperative chemotherapy. Results:There were 58 patients (44%) who underwent hepatectomy after an objective tumor response (group 1), 39 (30%) after tumor stabilization (group 2), and 34 (26%) after tumor progression (group 3). At the time of diagnosis, mean tumor size and number of metastases were similar in the 3 groups. No differences were observed regarding patient demographics, characteristics of the primary tumor, type of liver resection, and postoperative course. First line treatments were different between groups with a higher proportion of oxaliplatin- and/or irinotecan-based treatments in group 1 (P < 0.01). A higher number of lines of chemotherapy were used in group 2 (P = 0.002). Overall survival was 86%, 41%, and 28% at 1, 3, and 5 years, respectively. Five-year survival was much lower in group 3 compared with groups 1 and 2 (8% vs. 37% and 30%, respectively at 5 years, P < 0.0001). Disease-free survival was 3% compared with 21% and 20%, respectively (P = 0.02). In a multivariate analysis, tumor progression on chemotherapy (P < 0.0001), elevated preoperative serum CA 19–9 (P < 0.0001), number of resected metastases (P < 0.001), and the number of lines of chemotherapy (P < 0.04), but not the type of first line treatment, were independently associated with decreased survival. Conclusions:Liver resection is able to offer long-term survival to patients with multiple colorectal metastases provided that the metastatic disease is controlled by chemotherapy prior to surgery. Tumor progression before surgery is associated with a poor outcome, even after potentially curative hepatectomy. Tumor control before surgery is crucial to offer a chance of prolonged remission in patients with multiple metastases.

Is liver resection justified for patients with hepatic metastases from breast cancer

Objective:The purpose of this study was to examine our experience with hepatic resection (HR) in a relatively unselected group of patients with breast cancer liver metastases (BCLM). Background:Although medical therapies provide limited survival benefit (median survival, 3–15 months), inclusion of HR into the multimodality treatment of patients with BCLM remains controversial. Our approach has been to offer HR to all patients with BCLM, provided that curative hepatic resection was feasible and extrahepatic disease was controlled with medical and/or surgical therapy. Methods:Outcomes for 85 consecutive patients (all female, median age, 47 years) with BCLM treated with HR from 1984 to 2004 were reviewed. Extrahepatic metastases had been treated prior to HR or were synchronously present in 27 patients (32%). BCLM were solitary in 32 patients (38%) and numbered more than 3 in 26 patients (31%). The prognostic value of each study variable was assessed with log rank tests for univariate analysis and Cox proportional hazard models for multivariate analysis. Results:Within 60 days of major hepatectomy (≥3 segments, 54 patients) or minor hepatectomy (<3 segments, 31 patients), there was no mortality. The median hospital stay was 9 days with complications occurring in 26% of patients. Microscopically and macroscopically positive margins were present in 18% (R1) and 17% (R2) of patients. Following HR, 28 patients (33%) developed isolated hepatic recurrences, 12 of whom were treated with repeat hepatectomy. At a median follow-up interval of 38 months, 32 patients were alive, yielding median and 5-year overall survivals of 32 months and 37%. Median and 5-year disease-free survivals were 20 months and 21%. Study variables independently associated with poor survival were failure to respond to preoperative chemotherapy (P = 0.008), an R2 resection (P = 0.0001), and the absence of repeat hepatectomy (P = 0.01). Conclusions:For patients with BCLM, HR is safe and may provide a significant survival benefit over medical therapy alone. Response to preoperative chemotherapy, resection margin, and rehepatectomy for intrahepatic recurrence are key prognostic factors. Importantly, favorable outcomes can be achieved even in patients with medically controlled or surgically resectable extrahepatic disease, indicating that surgery should be considered more frequently in the multidisciplinary care of patients with BCLM.

Complete Pathologic Response After Preoperative Chemotherapy for Colorectal Liver Metastases: Myth or Reality?

PURPOSE Complete clinical response (CCR) of colorectal liver metastases (CLM) following chemotherapy is of limited predictive value for complete pathologic response (CPR) and cure of the disease. The objective of this study was to determine predictive factors of CPR as well as its impact on survival. PATIENTS AND METHODS From January 1985 to July 2006, 767 consecutive patients with CLM underwent liver resection after systemic chemotherapy. Patients with CPR were compared with patients without CPR. RESULTS Twenty-nine of 767 (4%) patients had CPR, and none of these 29 patients had CCR. Patients with CPR (mean age, 54 years) had a mean number of 3.3 metastases at diagnosis (mean size, 29.3 mm). Objective response and stable disease were observed in 79% and 21% of cases, respectively. Postoperative mortality rate was 0%. After a median follow-up of 52.2 months (range, 1.1 to 193.0 months), overall 5-year survival was 76% for patients with CPR compared with 45% for patients without CPR (P = .004). Independent predictive factors for CPR were: age <or= 60 years, size of metastases <or= 3 cm at diagnosis, carcinoembryonic antigen (CEA) level at diagnosis <or= 30 ng/mL, and objective response following chemotherapy. The probability of CPR ranged from 0.2% when all factors were absent to 30.9% when all were present. CONCLUSION CPR was observed in 4% of patients with CLM treated with preoperative chemotherapy. However, CPR may occur in almost one-third of objective responders age <or= 60 years with metastases <or= 3 cm and low CEA values. CPR is associated with uncommon high survival rates.

Cetuximab plus Gemcitabine-Oxaliplatin (GEMOX) in Patients with Refractory Advanced Intrahepatic Cholangiocarcinomas

Objectives: To assess the efficacy and safety of cetuximab in the palliative treatment of patients with intrahepatic cholangiocarcinomas (CCA) unresponsive to first-line gemcitabine-oxaliplatin (GEMOX) pretreatment. Methods: Nine patients (mean age: 54 years) with recurrent or unresectable CCA (6 peripheral and 3 hilar CCA, histologically proven) resistant to GEMOX received cetuximab 400 mg/m2 on day 1 then 250 mg/m2 weekly combined with gemcitabine 1,000 mg/m2 on day 1 and oxaliplatin 85 mg/m2 on day 2, every 3 weeks. Immunohistochemical detection of epidermal growth factor receptor (EGFR) and erbB-2, as well as EGFR gene copy number were assessed. Tumor response was measured using RECIST. Results: A total of 43 cycles were given (3–8 per patient). After 6 months, CT scans revealed 1 complete response, 1 partial response, 1 stable disease and 6 patients with disease progression. Median time to tumor progression and overall survival were 4 and 7 months, respectively. All patients relapsed (mean follow-up: 17 months). In 6 patients, death was not related to treatment. Toxicity included grade 3 neutropenia (n = 1) and acne-like rash (n = 7). In 7 of the 9 patients, EGFR was highly expressed in all tumor cells without gene amplification. No expression of erbB-2 was noted. Conclusion: Even in the absence of EGFR gene amplification, cetuximab + GEMOX is a well-tolerated palliative treatment in patients with advanced CCA. Adding cetuximab circumvents tumor resistance to GEMOX.

Tumor Marker Evolution: Comparison with Imaging for Assessment of Response to Chemotherapy in Patients with Colorectal Liver Metastases

BackgroundAs the real clinical significance of carcinoembryonic antigen (CEA) and carbohydrate antigen 19.9 (CA19.9) evolution during preoperative chemotherapy for colorectal liver metastases (CLM) is still unknown, we explored the correlation between biological and radiological response to chemotherapy, and their comparative impact on outcome after hepatectomy.MethodsAll patients resected for CLM at our hospital between 1990 and 2004 with the following eligibility criteria were included in the study: (1) preoperative chemotherapy, (2) complete resection of CLM, (3) no extrahepatic disease, and (4) elevated baseline tumor marker values. A 20% change of tumor marker levels while on chemotherapy was used to define biological response (decrease) or progression (increase). Correlation between biological and radiological response at computed tomography (CT) scan, and their impact on overall survival (OS) and progression-free survival (PFS) after hepatectomy were determined.ResultsAmong 119 of 695 consecutive patients resected for CLM who fulfilled the inclusion criteria, serial CEA and CA19.9 were available in 113 and 68 patients, respectively. Of patients with radiological response or stabilization, 94% had similar biological evolution for CEA and 91% for CA19.9. In patients with radiological progression, similar biological evolution was observed in 95% of cases for CEA and in 64% for CA19.9. On multivariate analysis, radiological response (but not biological evolution) independently predicted OS. However, progression of CA19.9, but not radiological response, was an independent predictor of PFS.ConclusionsIn patients with CLM and elevated tumor markers, biological response is as accurate as CT imaging to assess “clinical” response to chemotherapy. With regards to PFS, CA19.9 evolution has even better prognostic value than does radiological response. Assessment of tumor markers could be sufficient to evaluate chemotherapy response in a nonsurgical setting, limiting the need of repeat imaging.

Loss of Epidermal Growth Factor Receptor Expression in Lymph Node and Liver Metastases of Colon Carcinoma

TO THE EDITOR: We read with great interest the article by Scartozzi et al published in the December 1, 2004, issue of the Journal of Clinical Oncology. In their series, epidermal growth factor receptor (EGFR) status was positive in only 53% of colorectal tumors and its status in primary tumors did not correlate with EGFR expression in related metastatic sites. We would like to emphasize that using a different test of EGFR immunohistochemical detection, we also observed this discrepancy between primary colon carcinoma and liver metastases in a series of 40 patients (25 men, 15 women; mean age, 57.5 years). All patients underwent a first hepatectomy for liver metastases; second and third hepatic resections were performed in 14 and three patients, respectively. In addition, seven patients had tumor liver biopsy. Using CONFIRM anti-EGFR (3C6) primary antibody (Ventana Medical Systems; Illkirch, France) on a Ventana NexES immunohistochemistry staining platform (Ventana Medical Systems), we analyzed EGFR expression on 40 surgically resected colon adenocarcinomas, on the 27 metastatic regional lymph nodes, and on the 64 related liver metastases. Membranous EGFR expression was detected in 1% of the tumor cells of 38 colon carcinomas (95%), 23 metastatic lymph nodes (88%), and 51 liver metastases (79%). In our series, both primary tumors and related metastases (lymph node and liver) were positive for EGFR expression in 28 patients (73%). In six patients with a positive EGFR status in colon carcinoma, EGFR expression was detected either in lymph node or in liver metastases, as listed in Table 1. Taken together, these data point out the variability of EGFR detection using different immunohistochemical methods. Even in a series of patients with a high rate of EGFR-positive colon carcinomas, immunohistochemical expression of EGFR could be lost in the related metastases. Which sample—primary or metastic tumor—is the most adequate to determine a therapeutically relevant EGFR status is yet to be solved.

Sorafenib vs surgical resection for hepatocellular carcinoma with macrovascular invasion: A propensity score analysis

Sorafenib is the standard of care for patients with hepatocellular carcinoma (HCC) and macrovascular invasion (MVI), with limited survival. Retrospective surgical studies have reported prolonged survival in this situation. This study aimed to compare the overall survival of patients with HCC and MVI treated with surgical resection or sorafenib.

Adjuvant Gemcitabine-Oxaliplatin (GEMOX) after Curative Surgery in High-risk Patients with Cholangiocarcinoma

Background There is no standard adjuvant chemotherapy to prevent recurrent cholangiocarcinoma (CCA), a rare cancer with poor prognosis. We assessed the efficacy and safety of GEMOX on intrahepatic and hilar CCA with high-risk factors after curative surgery. Patients and Methods Twenty two patients (mean age: 57 years old) with CCA received 6 cycles of GEMOX: gemcitabine 1,000 mg/m2 on day 1 and oxaliplatin 85 mg/m2 on day 2, q3w after a curative surgery. Results All patients completed 6 cycles of GEMOX. EGFR membranous expression was present in 20 CCA. The 5-year survival rate was 56% (CI 95%: 25.7–85.4); 2-year disease free survival rate was 28% (CI 95%: 3.4–52.6). Median time to progression was 15 months. The rate of recurrence after surgery and chemotherapy was 63% (14/22). Two patients died of disease progression. Twelve patients received cetuximab/GEMOX at the time of relapse. Six died after 12 months (9–48 months), three are still alive suggesting a clinical applicability of EGFR inhibitors in CCA. Conclusion Adjuvant chemotherapy with GEMOX alone seems ineffective in intrahepatic and hilar CCA with a high risk of relapse. Additional studies including targeted therapies to circumvent such poor chemosensitivity are needed.