Conversion to resection of liver metastases from colorectal cancer with hepatic artery infusion of combined chemotherapy and systemic cetuximab in multicenter trial OPTILIV.

BACKGROUND: Systemic chemotherapy typically converts previously unresectable liver metastases (LM) from colorectal cancer to curative intent resection in ∼15% of patients. This European multicenter phase II trial tested whether hepatic artery infusion (HAI) with triplet chemotherapy and systemic cetuximab could increase this rate to 30% in previously treated patients. PATIENTS AND METHODS: Participants had unresectable LM from wt KRAS colorectal cancer. Main non-inclusion criteria were advanced extra hepatic disease, prior HAI and grade 3 neuropathy. Irinotecan (180 mg/m(2)), oxaliplatin (85 mg/m(2)) and 5-fluorouracil (2800 mg/m(2)) were delivered via an implanted HAI access port and combined with i.v. cetuximab (500 mg/m(2)) every 14 days. Multidisciplinary decisions to resect LM were taken after every three courses. The rate of macroscopic complete resections (R0 + R1) of LM, progression-free survival (PFS) and overall survival (OS) were computed according to intent to treat. RESULTS: The patient population consisted of 42 men and 22 women, aged 33-76 years, with a median of 10 LM involving a median of six segments. Up to 3 extrahepatic lesions of <1 cm were found in 41% of the patients. A median of six courses was delivered. The primary end point was met, with R0-R1 hepatectomy for 19 of the 64 previously treated patients, 29.7% (95% confidence interval 18.5-40.9). Grade 3-4 neutropenia (42.6%), abdominal pain (26.2%), fatigue (18%) and diarrhea (16.4%) were frequent. Objective response rate was 40.6% (28.6-52.3). Median PFS and OS reached 9.3 (7.8-10.9) and 25.5 months (18.8-32.1) respectively. Those with R0-R1 hepatectomy had a median OS of 35.2 months (32.6-37.8), with 37.4% (23.6-51.2) alive at 4 years. CONCLUSION: The coordination of liver-specific intensive chemotherapy and surgery had a high curative intent potential that deserves upfront randomized testing. PROTOCOL NUMBERS: EUDRACT 2007-004632-24, NCT00852228.

Five-year survival following hepatic resection after neoadjuvant therapy for nonresectable colorectal.

BACKGROUND: Surgical resection is the most effective treatment for colorectal liver metastases but only a minority of patients are candidates for a potentially curative resection. Our experience with neoadjuvant chemotherapy followed by resection and five years survival analysis of the patients treated is presented. METHODS: Between February of 1988 and September of 1996, 701 patients with unresectable colorectal liver metastases were treated with neoadjuvant chemotherapy. Four categories of nonresectable disease were defined: large size, ill location, multinodularity, and extrahepatic disease. Liver resection was performed in those patients whose disease became resectable. After resection, the patients were followed up every 3 months. A 5-year survival analysis by the different categories described was performed. RESULTS: Ninety-five patients (13.5%) were found to be resectable on reevaluation and underwent a potentially curative resection. There was no perioperative mortality, and the complication rate was 23%. As of December of 1999, 87 patients have completed 5 years of follow-up. The overall 5-year survival is 35% from the time of resection and 39% from the onset of chemotherapy. Respective 5-year survival rates are 60% for large tumors, 49% for ill-located lesions, 34% for multinodular disease, and 18% for liver metastases with extrahepatic disease. In this latter category, however, a 35% 5-year survival was found when all the patients with extrahepatic disease were analyzed rather than only those for whom extrahepatic disease was the main cause of nonresectability. CONCLUSIONS: Neoadjuvant chemotherapy enables liver resection in some patients with initially unresectable colorectal metastases. Long-term survival is similar to that reported for a priori surgical candidates.

Long-term survival of patients with unresectable colorectal cancer liver metastases following infusional chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin and surgery.

CONTEXT: Long-term survival of patients with metastatic colorectal cancer has been achieved only in patients who underwent complete resection of metastases. Such surgery could be performed in a greater proportion of patients if effective chemotherapy could downstage previously unresectable metastases. This approach has been limited by the low tumor response rate achieved with conventional chemotherapy. OBJECTIVE: We studied the outcome of patients with initially unresectable liver metastases from colorectal cancer treated with a three-drug chemotherapy regimen followed by liver metastases surgery whenever possible. PATIENTS AND METHODS: From March 1988 to June 1994, 151 patients with colorectal liver metastases were considered initially unresectable because of large tumor size (> 5 cm), multinodular (> 4) or ill-located metastases. All patients received fully ambulatory chemotherapy with 5-fluorouracil, leucovorin and oxaliplatin (chronotherapy in 83% of them). They were periodically reassessed for surgery by a joint medico-surgical team. RESULTS: In 151 patients, the size of liver metastases decreased by > 50% in 89 patients (59%) and median overall survival was 24 months (95% confidence interval (95% CI): 19-28 months), with 28% surviving at five years (20%-35%). Surgery with curative intent was attempted in 77 patients (51%), complete resection of liver metastases was achieved in 58 patients (38%). The median survival of the 77 operated patients was 48 months (25-71), with a five-year survival rate of 50% (38-61). CONCLUSION: This new strategy of combining effective chemotherapy with surgery apparently altered the natural history of unresectable colorectal cancer metastases.

Place of cryosurgery in the treatment of malignant liver tumors.

OBJECTIVE: The authors evaluate the results of cryosurgery in malignant liver tumors. SUMMARY BACKGROUND DATA: The outcome of primary or secondary liver tumors is poor when resection can not be achieved. Encouraging results of cryosurgery have been reported in unresectable liver tumors, but this treatment needs further evaluation of its efficacy in homogeneous groups of patients. METHODS: From 63 patients with malignant liver tumors with various histology treated by cryosurgery in a 2.5-year period, the authors evaluated the results of 34 patients with nonresectable hepatocellular carcinoma (9 patients) or nonresectable metastases from colorectal cancer (25 patients). Cryosurgery was used either as a single treatment (4 hepatocellular carcinomas, 5 metastases) or in association with liver resection (5 hepatocellular carcinomas, 20 metastases). Systemic chemotherapy was used routinely before surgery and after surgery. RESULTS: There was no intraoperative mortality. Mortality within 2 months was 3% and was unrelated to the procedure. Postoperative morbidity consisted of one sterile fluid collection and one biliary fistula (8%). At a mean follow-up of 16 months, (range, 2-27) local recurrence rate was 0% for hepatocellular carcinoma and 44% for metastases. Cumulative survival at 24 months was 63% and 52%, respectively, with 6 patients (67%) and 5 patients (20%) currently disease free. In the group of patients with metastases, survival was related to the size of the treated tumor (p = 0.06) and the absence of residual disease (p = 0.03). CONCLUSIONS: Cryosurgery is safe and increases the number of patients with unresectable liver malignancies in whom surgery can aim at eradicating the tumor. Local recurrence is observed more frequently for metastases than for hepatocellular carcinoma. The benefit in survival is related to the complete treatment of the tumoral disease.

[Tumors of the liver: morphological tests]. / Tumeurs du foie: examens morphologiques.

Benign or malignant liver tumors are frequent and various imaging modalities are available: ultrasonography, CT, MR. The aim of this review article is to define the indications for the various imaging modalities in the diagnosis, therapeutic decision and post-treatment follow-up of the various type of liver tumors.

Biweekly intensified ambulatory chronomodulated chemotherapy with oxaliplatin, fluorouracil, and leucovorin in patients with metastatic colorectal cancer.

PURPOSE: This study sought to determine the feasibility and antitumor efficacy of an intensified three-drug chronomodulated regimen with maximum delivery at 4:00 AM for fluorouracil (5-FU)-leucovorin (folinic acid [FA]) and at 4:00 PM for oxaliplatin (I-OHP). PATIENTS AND METHODS: Fifty patients with metastatic colorectal cancer were enrolled in the trial. The first treatment course consisted of daily administration of 5-FU (700 mg/m2/d), FA (300 mg/m2/d), and L-OHP (25 mg/m2/d) for 4 days with a multichannel programmable pump. Courses were repeated every 14 days, with 5-FU escalation by 100 mg/m2/d if toxicity was less than grade 2. RESULTS: World Health Organization (WHO)-modified grade 3 or 4 diarrhea (40% of patients and 7% of courses) or stomatitis (28% of patients and 4% of courses) or grade 2 cumulative peripheral sensitive neuropathy (28% of patients) were dose-limiting. Median 5-FU and L-OHP dose-intensities (DIs), were increased by 32% and 18%, respectively, as compared with our previous 5 days on-16 days off schedule. The overall objective response rate was 48% (95% confidence limits [CL], 34% to 62%), being 40% (24% to 57%) in 37 previously treated patients and 69% (48% to 90%) in 13 chemotherapy-naive patients. A 5-FU DI > 1,400 mg/m2/wk over four courses was associated with a near doubling of the response rate. Residual metastases were surgically removed in 13 patients (26%). Median progression-free survival and survival durations were 9.3 months (95% CL, 6.6 to 11.2) and 17.8 months (95% CL, 14.1 to 21.4), respectively. CONCLUSION: This highly effective fully ambulatory outpatient regimen deserves further testing in randomized trials both in chemotherapy-naive patients and before surgery to remove metastases.

A chronopharmacologic phase II clinical trial with 5-fluorouracil, folinic acid, and oxaliplatin using an ambulatory multichannel programmable pump. High antitumor effectiveness against metastatic colorectal cancer.

A significant increase in the dose intensity of chemotherapy with fluoropyrimidines and platinum complexes has resulted from selective circadian timing and/or circadian modulation of the infusion rate. The relevance of such chronopharmacologic strategy for improving the outcome of metastatic colorectal cancer was evaluated in an extended Phase II clinical trial involving 93 patients. Of these, 49% previously had received chemotherapy and/or radiation therapy. The drugs 5-fluorouracil (5-FU, 700 mg/m2/d) and folinic acid (FA, 300 mg/m2/d) combined with oxaliplatin (l-OHP, a nonnephrotoxic platinum complex, 25 mg/m2/d) were infused continuously for 5 days every 3 weeks. In a pilot randomized study, the infusion of all three drugs at a constant rate resulted in World Health Organization (WHO) Grade 3 or 4 toxicity in all four patients compared with no such toxicity in four patients if the infusion rate was modulated according to circadian rhythms. In this Phase II trial, drug delivery was modulated sinusoidally over the 24-hour day with peak flow rates at 4 AM for 5-FU and FA and at 4 PM for l-OHP, using an ambulatory programmable-in-time pump. All patients and 784 of 839 courses (93%) were evaluable for toxicity. Dose-limiting toxicities (WHO Grade 2 to 4) included diarrhea (19% of courses) and vomiting (35% of courses). In addition, WHO Grade 2 to 4 hematologic or mucosal toxicity, respectively, occurred in 2.5% and 7% of courses. Two toxic deaths were encountered. Peripheral sensory neuropathy led to discontinuation of l-OHP in 14 patients after 7 to 12 courses; it completely disappeared within 3 months. Fifty-four of the 93 patients had an objective response (58%; 95% confidence limits, 48% to 68%), irrespective of previous treatment or prior documented progression while receiving standard chemotherapy with 5-FU and FA or continuous 5-FU. Complete responses (CR) were seen in 6 patients (4 of which were proved histologically) and, after surgery, in 12 additional patients (overall CR rate, 18 of 93 [19%]; 95% confidence limits, 11% to 27%). Median progression-free survival (PFS) and overall survival were, respectively, 10 and 15 months, irrespective of prior therapy. Both PFS and survival were significantly longer in patients with a good performance status (PS, 0 or 1, by WHO criteria; respectively, 12 and 21 months) than in patients with poor PS (respectively, 8 and 10 months; P less than 0.01, by log-rank test). This chronopharmacologic protocol may have circumvented, to some extent, both the natural and acquired resistance of colorectal cancer to chemotherapy.

[Cancer of the breast and ultrasonographic nodule of the liver]. / Cancer du sein et nodule échographique du foie.

Metastases and angiomas are lesions which, because of their frequency, can be discovered in the liver on ultrasonographies performed on patients followed for breast cancer. This study was based on 109 patients with breast cancer and ultrasonographic nodules of the liver, generally corresponding to metastases (71 cases) or to angiomas (40 cases). The echogenicity of metastases (hypoechogenic) is so different from that of angiomas (hyperechogenic) that, in the great majority of cases, they can be distinguished on the basis of ultrasonography alone, thereby avoiding the systematic need for other complementary diagnostic investigations.

Utility of operative ultrasound in the surgical management of liver tumors.

In this study the utility of operative ultrasound in the surgical management of 98 consecutive patients with liver and gastrointestinal tumors was assessed. All patients had preoperative work-up including ultrasound study of the liver as well as selective hepatic arteriography (50 patients) and computerized tomography of the liver (45 patients). At surgery, inspection and palpation of the liver as well as operative ultrasound examination were performed in all cases. Fifty-six patients were known to have liver tumors before operation, while 42 patients had their liver examined as part of the treatment of a primary gastrointestinal malignancy. A total of 126 liver tumors were found in 58 patients, all of whom were confirmed histologically. Eighteen nodules unsuspected before operation were found at surgery--nine by inspection and palpation of the liver, and nine others that were nonpalpable were found by operative ultrasound only. Eighteen lesions that were missed by all diagnostic modalities were found as secondary lesions on pathologic examination of the resected specimens. In addition to diagnostic applications, operative ultrasound was useful in localizing nodules and permitting guided biopsies deep in the hepatic parenchyma. In eight cases, segmental resections were performed with operative ultrasound to localize the plane of section and to catheterize the intrahepatic portal vein branch afferent to the tumor in order to perform balloon catheter occlusion of the vessel for control of bleeding. Operative ultrasound was found to be important in the surgical management of 19 of 98 patients (19%).

Intraoperative ultrasonographic study of the liver. Methods and anatomic results.

In this study, we have reported our experience with the use of intraoperative ultrasonography in the field of liver surgery. Using the method, the intrahepatic segmental pedicles can be precisely located and thus, segmentectomies can be performed in an anatomic way. The technique allows the most economic parenchymal resection in cirrhotic patients which may be important for prevention of postoperative liver insufficiency.

[Peroperative echography in hepatobiliary surgery]. / L'échographie per-opératoire en chirurgie hépato-biliaire.

Intra-operative echography provides precise information on anatomy of the liver and accurately locates hepatic tumours, even small ones, thereby improving the operative strategy. It is most useful in biliary surgery for detection and treatment of intrahepatic lithiasis. By displaying undetected hepatic metastases, echography of the liver is of considerable value in surgery of common tumours of the digestive tract.

[Value of echotomography for the diagnosis of lithiasis of the common bile duct]. / Valeur de l'échotomographie pour le diagnostic de lithiase de la voie biliaire principale.

The accuracy of ultrasonography (US) for the diagnosis of cholelithiasis and for dilatation of the intra- and extra-hepatic biliary tree is well known. However, the value of US for the diagnosis of common bile duct stones remains poorly defined. We performed a prospective study in 100 patients who were referred for endoscopic retrograde cholangiopancreatography (ERCP); all the examinations were carried out by the same sonographist in the 24 h preceding the ERCP. Fifty patients had choledocholithiasis, 20 patients had obstruction of the bile ducts without lithiasis and the common bile duct (CBD) was free in 30 patients. The sensitivity of US for the diagnosis of choledocholithiasis was 40 p. 100, the specificity 90 p. 100. The positive and negative predictive values of the "CBD stone" sign was 80 p. 100 and 60 p. 100 respectively. In a total of 30 false negatives, the CBD could not be explored in 4 cases, dilatation of the CBD was missed in one case, and obstruction of the CBD by an other disease was diagnosed in 2; in all the other cases, US was able to appreciate the CBD size as well as the ERCP. In the 20 patients with an obstructed CBD but without choledocholithiasis, US diagnosed a stone in 5 cases. Age, serum bilirubin, existence of a previous cholecystectomy, technical difficulties, stone size were comparable in patients with true positive tests and in patients with false negative tests. However the diagnosis of choledocholithiasis was more frequently achieved in patients with dilated CBD over 10 mm (p less than 0.05) and in patients with multiple stones.(ABSTRACT TRUNCATED AT 250 WORDS)

Diaphragm dysfunction induced by upper abdominal surgery. Role of postoperative pain.

The effects of upper abdominal surgery on diaphragmatic function were studied in 5 patients. During quiet tidal breathing, the volume displacement of the abdomen within the tidal volume (Vab/Vt) and the ratio of abdominal and transdiaphragmatic pressure changes (delta Pab/delta Pdi), taken as an index of the diaphragmatic contribution to the breathing process, decreased significantly on the first postoperative day (p less than 0.001); in 2 patients, a cephalad paradoxical motion of the diaphragm during inspiration was observed. Diaphragmatic dysfunction also occurred during maximal inspiratory efforts as shown by the significant fall in maximal static transdiaphragmatic pressure (Pdimax) and cephalocaudal diaphragmatic displacement on the first (p less than 0.001) and third (p less than 0.001) postoperative days. On the first postoperative day, opiate epidural analgesia did not modify Vab/VT, delta Pab/delta Pdi, and Pdimax. These parameters spontaneously returned towards control values on the seventh postoperative day. We conclude that upper abdominal surgery induces a marked diaphragmatic dysfunction lasting about 1 wk and that it is not suppressed by postoperative pain relief. The mechanism of this dysfunction remains to be determined. It may be the main cause of the postoperative pulmonary restrictive pattern.

Endovascular electrocoagulation with a bipolar electrode and alternating current: a follow-up study in dogs.

Endovascular electrocoagulation of the anterior tibial artery in dogs was performed with two different bipolar electrodes. Follow-up showed revascularization when a short-tip electrode was used, but no revascularization when a long-tip electrode was used. Histologic study showed complete occlusion of the artery by an organized thrombus adherent to the vessel wall.

Does total parenteral nutrition induce gallbladder sludge formation and lithiasis?

To assess the prevalence of sludge formation and lithiasis during total parenteral nutrition, serial biliary ultrasonographic studies were performed during and after i.v. nutrition periods in 23 selected adult gastroenterological patients. All patients were free of hepatobiliary disease before i.v. nutrition. Initial sonograms of 19 patients taken at the 12th day +/- 2 days (mean +/- SEM) of i.v. nutrition were normal. Initial studies for the 4 remaining patients, which were performed on the 39th day +/- 10 days of i.v. therapy (p less than 0.001), showed gallbladder sludge but did not demonstrate lithiasis. Serial ultrasonographic studies indicated that the percentage of sludge-positive patients during parenteral nutrition increased from 6% during the first 3 wk to 50% between the fourth and the sixth weeks and reached 100% in patients receiving i.v. nutritional therapy for greater than 6 wk. Gallstone formation was demonstrated in 6 of 14 sludge-forming patients but was not observed in patients who were sludge-negative. Three of the 6 stone-forming patients underwent cholecystectomy because of complications secondary to cholelithiasis after a mean 43-day course of parenteral nutrition. Analysis of bile from these patients revealed thick bile-containing cholesterol crystals and small stones of mixed bilirubin-cholesterol type. Ultrasonographic studies were obtained for sludge-positive patients after the parenteral nutrition period. Sludge positivity decreased from 88% during the first 3 wk of oral refeeding to 0% by the end of the fourth week. This study, therefore, strongly suggests that bowel rest and bile stasis during parenteral nutrition lead to production of sludge, which can result in eventual gallstone formation. Consequently, during parenteral nutrition exceeding 1 mo, gallbladder stasis should be palliated to prevent cholelithiasis formation.