Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23): a multicentre, randomised, open-label, phase 3 trial.

BACKGROUND: Treatment of locally advanced rectal cancer with chemoradiotherapy, surgery, and adjuvant chemotherapy controls local disease, but distant metastases remain common. We aimed to assess whether administering neoadjuvant chemotherapy before preoperative chemoradiotherapy could reduce the risk of distant recurrences. METHODS: We did a phase 3, open-label, multicentre, randomised trial at 35 hospitals in France. Eligible patients were adults aged 18-75 years and had newly diagnosed, biopsy-proven, rectal adenocarcinoma staged cT3 or cT4 M0, with a WHO performance status of 0-1. Patients were randomly assigned (1:1) to either the neoadjuvant chemotherapy group or standard-of-care group, using an independent web-based system by minimisation method stratified by centre, extramural extension of the tumour into perirectal fat according to MRI, tumour location, and stage. Investigators and participants were not masked to treatment allocation. The neoadjuvant chemotherapy group received neoadjuvant chemotherapy with FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2, and fluorouracil 2400 mg/m2 intravenously every 14 days for 6 cycles), chemoradiotherapy (50 Gy during 5 weeks and 800 mg/m2 concurrent oral capecitabine twice daily for 5 days per week), total mesorectal excision, and adjuvant chemotherapy (3 months of modified FOLFOX6 [intravenous oxaliplatin 85 mg/m2 and leucovorin 400 mg/m2, followed by intravenous 400 mg/m2 fluorouracil bolus and then continuous infusion at a dose of 2400 mg/m2 over 46 h every 14 days for six cycles] or capecitabine [1250 mg/m2 orally twice daily on days 1-14 every 21 days]). The standard-of-care group received chemoradiotherapy, total mesorectal excision, and adjuvant chemotherapy (for 6 months). The primary endpoint was disease-free survival assessed in the intention-to-treat population at 3 years. Safety analyses were done on treated patients. This trial was registered with EudraCT (2011-004406-25) and ClinicalTrials.gov (NCT01804790) and is now complete. FINDINGS: Between June 5, 2012, and June 26, 2017, 461 patients were randomly assigned to either the neoadjuvant chemotherapy group (n=231) or the standard-of-care group (n=230). At a median follow-up of 46·5 months (IQR 35·4-61·6), 3-year disease-free survival rates were 76% (95% CI 69-81) in the neoadjuvant chemotherapy group and 69% (62-74) in the standard-of-care group (stratified hazard ratio 0·69, 95% CI 0·49-0·97; p=0·034). During neoadjuvant chemotherapy, the most common grade 3-4 adverse events were neutropenia (38 [17%] of 225 patients) and diarrhoea (25 [11%] of 226). During chemoradiotherapy, the most common grade 3-4 adverse event was lymphopenia (59 [28%] of 212 in the neoadjuvant chemotherapy group vs 67 [30%] of 226 patients in the standard-of-care group). During adjuvant chemotherapy, the most common grade 3-4 adverse events were lymphopenia (18 [11%] of 161 in the neoadjuvant chemotherapy group vs 42 [27%] of 155 in the standard-of-care group), neutropenia (nine [6%] of 161 vs 28 [18%] of 155), and peripheral sensory neuropathy (19 [12%] of 162 vs 32 [21%] of 155). Serious adverse events occurred in 63 (27%) of 231 participants in the neoadjuvant chemotherapy group and 50 (22%) of 230 patients in the standard-of-care group (p=0·167), during the whole treatment period. During adjuvant therapy, serious adverse events occurred in 18 (11%) of 163 participants in the neoadjuvant chemotherapy group and 36 (23%) of 158 patients in the standard-of-care group (p=0·0049). Treatment-related deaths occurred in one (<1%) of 226 patients in the neoadjuvant chemotherapy group (sudden death) and two (1%) of 227 patients in the standard-of-care group (one sudden death and one myocardial infarction). INTERPRETATION: Intensification of chemotherapy using FOLFIRINOX before preoperative chemoradiotherapy significantly improved outcomes compared with preoperative chemoradiotherapy in patients with cT3 or cT4 M0 rectal cancer. The significantly improved disease-free survival in the neoadjuvant chemotherapy group and the decreased neurotoxicity indicates that the perioperative approach is more efficient and better tolerated than adjuvant chemotherapy. Therefore, the PRODIGE 23 results might change clinical practice. FUNDING: Institut National du Cancer, Ligue Nationale Contre le Cancer, and R&D Unicancer.

Palliation of dysphagia in metastatic oesogastric cancers: An international multidisciplinary position.

Malignant dysphagia is the most common symptom in advanced oesogastric cancers patients. Relief of dysphagia allows quality of life improvement, nutritional replenishment and potentially improves prognosis. Chemotherapy alone is effective and should be prioritised in patients with metastatic disease a good performance status, and its impact on dysphagia should be determined before further interventions are planned. Regarding local treatments, the insertion of a covered self-expandable metallic stent is the most commonly used alternative, as it allows for the rapid relief of severe dysphagia. Although several randomised trials have highlighted the role of oesophageal brachytherapy, this technique is often not easily accessible. Contemporary trials are ongoing to better define the role of external radiation therapy. While awaiting these results, external radiation therapy can be considered as a second-best option for patients with a life-expectancy > 3 months. It is important to offer nutritional support and to integrate quality of life measures in the palliative management of dysphagia. This multidisciplinary international position paper aims to propose a decision-making process and highlight randomised trials for the management of malignant dysphagia in metastatic oesogastric cancer patients.

Sorafenib alone vs. sorafenib plus GEMOX as 1st-line treatment for advanced HCC: the phase II randomised PRODIGE 10 trial.

BACKGROUND: Sorafenib remains one major first-line therapeutic options for advanced hepatocellular carcinoma (aHCC), with modest efficacy. We investigated the addition of gemcitabine and oxaliplatin (GEMOX) to sorafenib in aHCC patients. METHODS: Our multicentre phase II trial randomised aHCC first-line patients to sorafenib (400 mg BID) or sorafenib-GEMOX every 2 weeks (1000 mg/m2 gemcitabine; 100 mg/m2 oxaliplatin). Primary endpoint was the 4-month progression-free survival (PFS) rate. RESULTS: Ninety-four patients were randomised (sorafenib-GEMOX: n = 48; sorafenib: n = 46). Median age was 64 years, PS 0 (69%) or 1 (31%), 63% patients had cirrhosis, 29% portal vein thrombosis and 70% extra-hepatic disease. Median duration of sorafenib treatment was 4 months (1-51); median number of GEMOX cycles was 7 (1-16). The 4-month PFS rates were 64% and 61% in the sorafenib-GEMOX and sorafenib arms, respectively; median PFS and OS were 6.2 (95% CI: 3.8-6.8) and 13.5 (7.5-16.2) months, and 4.6 (3.9-6.2) months and 14.8 (12.2-22.2), respectively. The ORR/DCR were 9%/70% and 15%/77% in the sorafenib-GEMOX and sorafenib alone arms, respectively. Main toxicities were (sorafenib-GEMOX/sorafenib) neutropenia (23%/0), thrombocytopenia (33%/0), diarrhoea (18%/9), peripheral neuropathy (5%/0) and hand-foot syndrome (5%/18). CONCLUSIONS: Addition of GEMOX had an inpact on ORR and was well-tolerated as frontline systemic therapy. The benefit on PFS seems moderate; no subsequent study was planned.

Postoperative hepatic arterial chemotherapy in high-risk patients as adjuvant treatment after resection of colorectal liver metastases - a randomized phase II/III trial - PACHA-01 (NCT02494973).

BACKGROUND: After curative-intent surgery for colorectal liver metastases (CRLM), liver recurrence occurs in more than 60% of patients, despite the administration of perioperative or adjuvant chemotherapy. This risk is even higher after resection of more than three CRLM. As CRLM are mostly supplied by arterial blood flow, hepatic arterial infusion (HAI) of chemotherapeutic agents after resection of CRLM is an attractive approach. Oxaliplatin-based HAI chemotherapy, in association with systemic fluoropyrimidines, has been shown to be safe and highly active in patients with CRLM. In a retrospective series of 98 patients at high risk of hepatic recurrence (≥4 resected CRLM), adjuvant HAI oxaliplatin combined with systemic chemotherapy was feasible and significantly improved disease-free survival compared to adjuvant, 'modern' systemic chemotherapy alone. METHODS/DESIGN: This study is designed as a multicentre, randomized, phase II/III trial. The first step is a non-comparative randomized phase II trial (power, 95%; one-sided alpha risk, 10%). Patients will be randomly assigned in a 1:1 ratio to adjuvant systemic FOLFOX (control arm) or adjuvant HAI oxaliplatin plus systemic LV5FU2 (experimental arm). A total 114 patients will need to be included. The main objective of this trial is to evaluate the potential survival benefit of adjuvant HAI with oxaliplatin after resection of at least 4 CRLM (primary endpoint: 18-month hepatic recurrence-free survival rate). We also aim to assess the feasibility of delivering at least 4 cycles of HAI (or i.v.) oxaliplatin after surgical treatment of at least 4 CRLM, the toxicity (NCI-CTC v4.0) of adjuvant HAI plus systemic chemotherapy, including HAI catheter-related complications, compared to systemic chemotherapy alone, and the efficacy of adjuvant HAI on hepatic and extra-hepatic recurrence-free (survival and overall survival). DISCUSSION: If 18-month hepatic recurrence-free survival is greater than 50% in the experimental arm, the study will be pursued in phase III, for which the primary endpoint will be 3-year recurrence-free survival rate. Patients randomized in the phase II will be included in the phase III, with an additional number of 106 patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02494973 . Trial registration date: July 10, 2015.

Peritoneal and extraperitoneal relapse after previous curative treatment of peritoneal metastases from colorectal cancer: What survival can we expect?

INTRODUCTION: Over the last 20 years, complete cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) dramatically increased the survival of patients with colorectal peritoneal metastases (CRPM). However, despite better knowledge of the disease, around 70% of patients relapse after CRS with HIPEC. This study was designed to analyse the pattern of recurrence and the outcomes of different treatment modalities. METHODS: Patients relapsing after CRS plus HIPEC for CRPM were selected from a prospective database. The impact of iterative curative-intent treatments was analysed using Kaplan-Meier estimates and multivariate Cox regression models. RESULTS: Between April 1993 and December 2014, 190 of 274 (69%) patients previously treated by CRS plus HIPEC developed relapse, as an isolated peritoneal recurrence (31%), isolated distant recurrence (35%), or multisite recurrence (34%). The curative-intent treatment rate was 48% for isolated peritoneal recurrences, 49% for isolated distant recurrences and 22% for multisite recurrences (p = 0.002). From the diagnosis of relapse, 3- and 5-year overall survival were 77% and 46% after curative-intent treatment and 14% and 4.7% after non-curative treatment, with median survival of 59.7 and 18.3 months (log-rank p < 0.0001), respectively. Regression analysis identified the initial extent of CRPM (hazard ratio [HR]: 2.25; p < 0.0001), iterative curative-intent treatment (HR: 0.22; p < 0.0001) and disease-free interval (HR: 1.77; p = 0.01) as independent predictors of prolonged survival. CONCLUSIONS: Iterative curative-intent treatment can be performed in up to 40% of patients with relapse after CRS and HIPEC for CRPM, and is associated with prolonged survival in selected patients.

Conversion to Complete Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Malignant Peritoneal Mesothelioma After Bidirectional Chemotherapy.

BACKGROUND: This report aims to describe preliminary results concerning secondary resectability after bidirectional chemotherapy for initially unresectable malignant peritoneal mesothelioma (MPM). METHODS: Between January 2013 and January 2016, 20 consecutive patients treated for diffuse MPM not suitable for upfront surgery received bidirectional chemotherapy associating intraperitoneal and systemic chemotherapy. Evaluation of the response to chemotherapy was assessed clinically and by laparoscopy. RESULTS: The median peritoneal cancer index (PCI) score at staging laparoscopy was 27 (range 15-39). Altogether, 118 intraperitoneal chemotherapy cycles were administered without any specific adverse catheter-related event. Concerning tolerance, 85% of the patients experienced no pain or mild pain during chemotherapy administration. The clinical response rate was 60% after a median of three chemotherapy cycles. At laparoscopic reevaluation, the median PCI was 18 (range 0-35), and a secondary resectability was considered for 55% of the patients. Complete cytoreduction surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC) was finally achieved for 10 patients (50%), with a median intraoperative PCI score of 14 (range 6-30). After a median follow-up period of 18 months, the 2-year overall survival rate was 83.3% for the patients treated by CRS followed by HIPEC and 44% for the patients treated by bidirectional chemotherapy. CONCLUSION: Bidirectional chemotherapy is a promising, well-tolerated treatment capable of increasing the resection rate for selected patients with diffuse MPM initially considered as unresectable or borderline resectable. For patients with definitively unresectable disease, bidirectional chemotherapy achieves a higher clinical response rate.

Prognostic Value of Sterilized Lymph Nodes After Preoperative Chemoradiotherapy for Patients with ypN0 Rectal Cancer.

BACKGROUND: Patients with ypN0 rectal cancer who have received preoperative chemoradiotherapy can be divided into those who initially were node negative and those whose positive nodes have been sterilized by preoperative therapy. The long-term prognosis for ypN0 patients with sterilized lymph nodes (LNS) is unknown. This study aimed to assess the prognostic value of LNS after preoperative chemoradiotherapy for patients with ypN0 rectal cancer. METHODS: From January 2007 to March 2014, 206 patients with ypN0 tumors of the mid or lower rectum treated by chemoradiotherapy and radical surgery were enrolled in the study. Of these 206 patients, 49 had ypN0 tumors with LNS (LNS+ group), and 157 had ypN0 tumors without LNS (LNS- group). The patients in both groups were comparable in terms of tumor characteristics, type of chemoradiotherapy, type of surgery, R0 resection rate, and postoperative complication rate. RESULTS: The mean follow-up period was 40.5 ± 27 months. The 1- and 3-year OS rates in the LNS+ group were respectively 100 and 95.5% versus 99.4 and 91.6% in the LNS- group (P = 0.549). The 1- and 3-year DFS rates in the LNS+ group were respectively 100 and 94.2% versus 94.7 and 87.1% in the LNS- group (P = 0.117). The multivariate analysis showed that the presence of LNS did not affect OS (P = 0.918) or DFS (P = 0.209). CONCLUSIONS: The prognosis is excellent for patients with ypN0 rectal cancer who have LNS after preoperative chemoradiotherapy. The presence of LNS in ypN0 rectal cancer patients after chemoradiotherapy should not be considered a factor for a poor prognosis.

Intra-arterial therapies for colorectal cancer liver metastases (radioembolization excluded).

During the past 20 years, advances in systemic therapies have improved overall survival of patients with Colorectal cancer Liver metastases (CRLM) from 6 to 24 months. By reaching CRLM via their preferential arterial vascularization, hepatic arterial infusion of chemotherapy (HAIC) has demonstrated improvement in response rate and deepness of response. Improvement in deepness of response is potentially helpful to convert no surgical patient to surgery. Recent HAIC regimens, including HAIC-FUDR plus systemic oxaliplatin/irinotecan, or HAIC-oxaliplatin plus systemic 5FU and cetuximab yielded a 92% and 90% response rate respectively, and conversion to R0 surgery in 47% and 42% of patients, respectively. When HAIC delivered a drug ineffective through intravenous delivery, this rechallenge provided 62% response rate for HAIC. Nowadays, port-catheter implanted percutaneously by radiologists has 95% feasibility with primary patency equivalent to that of surgically implanted catheters, and secondary patency superior after radiologic revision. Retrospective studies demonstrated prolonged DFS of HAIC over IV chemotherapy in the adjuvant setting after surgery of CRLM. Drug eluting beads loaded with irinotecan (DEBIRI) were developed as drug carrier and embolization platform for treatment of CRLM by chemoembolization. DEBIRI allows for a very high level of SN-38 (SN-38 is the active compound of irinotecan) and a very high rate of complete l response at pathologic studies of treated metastases. DEBIRI was compared to systemic FOLFIRI in a phase III randomized trial including 74 patients with benefit in overall survival and disease-free survival.

Systemic treatment of advanced hepatocellular carcinoma: from disillusions to new horizons.

Hepatocellular carcinoma (HCC) is an aggressive malignancy, which accounts for a third of all cancer deaths globally each year. The management of patients with HCC is complex, as both the tumour stage and any underlying liver disease must be considered conjointly. Since the approval of sorafenib in advanced HCC, several phase III clinical trials have failed to demonstrate any superiority over sorafenib in the frontline setting, and no agent has been shown to impact outcomes after sorafenib failure. This review will focus on the range of experimental therapeutics for patients with advanced HCC and highlight the successes and failures of these treatments as well as areas for future development. Specifics such as dose limiting toxicity and safety profile in patients with liver dysfunction related to the underlying chronic liver disease should be considered when developing therapies in HCC. Finally, robust validated and reproducible surrogate end-points as well as predictive biomarkers should be defined in future randomised trials.

Comparison of complete pathologic response and hepatic injuries between hepatic arterial infusion and systemic administration of oxaliplatin in patients with colorectal liver metastases.

BACKGROUND: Whether hepatic arterial infusion (HAI) of oxaliplatin influences the rates of complete pathologic response (CPR) and severe oxaliplatin-related lesions (SOxL) in patients with colorectal liver metastases (CRLM) is unknown. This study aimed to compare the incidence of CPR and SOxL between systemic (intravenous, IV) and HAI administration. METHODS: All patients with initially unresectable CRLM who had undergone hepatic resection in two expert centers between 2004 and 2010 after at least 6 cycles of oxaliplatin-based chemotherapy administered either via HAI (n = 18) or IV (n = 50) were included. The presence of CPR and SOxL were evaluated by two pathologists. A 1:2 case match using a propensity score was used. RESULTS: A CPR was observed significantly more often after HAI (33 vs. 10 %, P = 0.03). However, SOxL had occurred more frequently in patients in the HAI group versus the IV group, 66 and 20 %, respectively (P < 0.001). On a well-balanced cohort, HAI was associated with higher chance of CPR (odds ratio 9.33, 95 % confidence interval 1.59-54.7) but also higher risk of SOxL (odds ratio 13.7, 95 % confidence interval 3.08-61.3). A CPR markedly enhanced overall survival (OS) and disease-free survival (median OS of 114 vs. 42 months, P = 0.02; median disease-free survival of 51 vs. 12 months, P = 0.002). Patients with SOxL did not experience different outcome (median OS of 42 vs. 50 months, respectively; P = 0.92) CONCLUSIONS: HAI of oxaliplatin increases the likelihood of a CPR at the cost of a higher incidence of SOxL in patients with initially unresectable CRLM.

Surgery alone versus chemoradiotherapy followed by surgery for stage I and II esophageal cancer: final analysis of randomized controlled phase III trial FFCD 9901.

PURPOSE: Although often investigated in locally advanced esophageal cancer (EC), the impact of neoadjuvant chemoradiotherapy (NCRT) in early stages is unknown. The aim of this multicenter randomized phase III trial was to assess whether NCRT improves outcomes for patients with stage I or II EC. METHODS: The primary end point was overall survival. Secondary end points were disease-free survival, postoperative morbidity, in-hospital mortality, R0 resection rate, and prognostic factor identification. From June 2000 to June 2009, 195 patients in 30 centers were randomly assigned to surgery alone (group S; n = 97) or NCRT followed by surgery (group CRT; n = 98). CRT protocol was 45 Gy in 25 fractions over 5 weeks with two courses of concomitant chemotherapy composed of fluorouracil 800 mg/m(2) and cisplatin 75 mg/m(2). We report the long-term results of the final analysis, after a median follow-up of 93.6 months. RESULTS: Pretreatment disease was stage I in 19.0%, IIA in 53.3%, and IIB in 27.7% of patients. For group CRT compared with group S, R0 resection rate was 93.8% versus 92.1% (P = .749), with 3-year overall survival rate of 47.5% versus 53.0% (hazard ratio [HR], 0.99; 95% CI, 0.69 to 1.40; P = .94) and postoperative mortality rate of 11.1% versus 3.4% (P = .049), respectively. Because interim analysis of the primary end point revealed an improbability of demonstrating the superiority of either treatment arm (HR, 1.09; 95% CI, 0.75 to 1.59; P = .66), the trial was stopped for anticipated futility. CONCLUSION: Compared with surgery alone, NCRT with cisplatin plus fluorouracil does not improve R0 resection rate or survival but enhances postoperative mortality in patients with stage I or II EC.

A simple tumor load-based nomogram for surgery in patients with colorectal liver and peritoneal metastases.

BACKGROUND: The decision to perform optimal surgery when peritoneal metastases (PM) are associated with liver metastases (LM) is extremely complex. No guidelines exist. The purpose of this study was to present a simple and useful statistical tool that generates a graphical calculator (nomogram) to help the clinician rapidly estimate individualized patient-specific survival before undergoing optimal surgery. MATERIALS AND METHODS: An analysis of 287 patients with liver metastasis (LM), 119 patients with peritoneal metastasis (PM), and 37 patients with LM + PM, who underwent optimal surgery plus chemotherapy between 1995 and 2010 was performed. A minimal number of parameters were taken into account to obtain a nomogram that would be very simple to use. With the overall tumor load as the main prognostic factor, we included the number of lesions for LM and the peritoneal carcinomatosis score (PCI) for PM. The Cox model was used to generate the nomogram. RESULTS: The 5-year overall survival was, respectively, 38.5, 36.5, and 26.4 % in the LM group, the PM group, and the LM + PM group. The summation of 3 parameters (the number of LM, the PCI, and the type of surgery [liver resection, HIPEC, or both]), makes it easy to calculate a score that graphically corresponds to an estimation of survival after optimal surgery (nomogram). It can be used for LM alone, PM alone, or both. CONCLUSIONS: A graphic nomogram that is simple to calculate and easy to use enables us to rapidly appreciate the prognosis of patients according to the number of LM, the PCI, or both. This nomogram must be validated in prospective studies in other tertiary centers.

Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISK-PS study.

PURPOSE: Brivanib is a selective dual inhibitor of vascular endothelial growth factor and fibroblast growth factor receptors implicated in tumorigenesis and angiogenesis in hepatocellular carcinoma (HCC). An unmet medical need persists for patients with HCC whose tumors do not respond to sorafenib or who cannot tolerate it. This multicenter, double-blind, randomized, placebo-controlled trial assessed brivanib in patients with HCC who had been treated with sorafenib. PATIENTS AND METHODS: In all, 395 patients with advanced HCC who progressed on/after or were intolerant to sorafenib were randomly assigned (2:1) to receive brivanib 800 mg orally once per day plus best supportive care (BSC) or placebo plus BSC. The primary end point was overall survival (OS). Secondary end points included time to progression (TTP), objective response rate (ORR), and disease control rate based on modified Response Evaluation Criteria in Solid Tumors (mRECIST) and safety. RESULTS: Median OS was 9.4 months for brivanib and 8.2 months for placebo (hazard ratio [HR], 0.89; 95.8% CI, 0.69 to 1.15; P = .3307). Adjusting treatment effect for baseline prognostic factors yielded an OS HR of 0.81 (95% CI, 0.63 to 1.04; P = .1044). Exploratory analyses showed a median time to progression of 4.2 months for brivanib and 2.7 months for placebo (HR, 0.56; 95% CI, 0.42 to 0.76; P < .001), and an mRECIST ORR of 10% for brivanib and 2% for placebo (odds ratio, 5.72). Study discontinuation due to treatment-related adverse events (AEs) occurred in 61 brivanib patients (23%) and nine placebo patients (7%). The most frequent treatment-related grade 3 to 4 AEs for brivanib included hypertension (17%), fatigue (13%), hyponatremia (11%), and decreased appetite (10%). CONCLUSION: In patients with HCC who had been treated with sorafenib, brivanib did not significantly improve OS. The observed benefit in the secondary outcomes of TTP and ORR warrants further investigation.

Adjuvant chemotherapy after resection of colorectal liver metastases in patients at high risk of hepatic recurrence: a comparative study between hepatic arterial infusion of oxaliplatin and modern systemic chemotherapy.

INTRODUCTION: After curatively intended surgery for colorectal liver metastases, liver recurrences occur in more than 60% of patients, despite the administration of adjuvant systemic chemotherapy. The aim of this study was to assess the benefit of combined adjuvant hepatic arterial infusion (HAI) and intravenous (IV) 5-FU compared with standard modern adjuvant IV chemotherapy in patients at high risk of hepatic recurrence. PATIENTS AND METHODS: From January 2000 to December 2009, 98 patients, who had undergone curative resection of at least 4 colorectal liver metastases, were selected from a prospective database. Among them, 44 (45%) had received postoperative HAI combined with systemic 5-FU (HAI group) and 54 (55%) had received "modern" systemic chemotherapy (IV group). RESULTS: The 2 groups were similar in terms of age, sex, the stage of the primary, and the administration of preoperative chemotherapy. The median number of HAI cycles received per patient was 7 [range, 1-12]. Twenty-nine patients (66%) had received at least 6 cycles of HAI oxaliplatin, and 22 patients (50%) had received the full planned treatment. For the remaining 22 patients (50%), HAI chemotherapy had been discontinued because of toxicity (n = 8), HAI catheter dysfunction (n = 6), an early recurrence (n = 6), and patient's refusal (n = 2). After a median follow-up of 60 months (51-81 months), 3-year overall survival was slightly higher in the HAI group (75% vs 62%, P = 0.17). Three-year disease-free survival was significantly longer in patients in the HAI group than those in the IV group (33% vs 5%, P < 0.0001). In the multivariate analysis, adjuvant HAI chemotherapy and an R0 resection margin status were the only independent predictive factors for prolonged disease-free survival. CONCLUSIONS: Postoperative HAI oxaliplatin combined with systemic chemotherapy after curatively intended surgery of colorectal liver metastases is feasible and may significantly improve disease-free survival of patients at high risk of hepatic recurrence compared with adjuvant modern systemic chemotherapy alone. These results should be confirmed in a randomized study.

Liver/biliary injuries following chemoembolisation of endocrine tumours and hepatocellular carcinoma: lipiodol vs. drug-eluting beads.

BACKGROUND & AIMS: Transarterial chemoembolisation (TACE) is usually performed by injecting an emulsion of a drug and iodised oil. Drug-eluting beads (DEBs) have undeniable pharmacological advantages by offering simultaneous embolisation and sustained release of the drug to the tumour. No data are currently available on liver/biliary injury following DEB-TACE. This study describes and compares liver/biliary injuries encountered with TACE in tumours developed in cirrhotic (hepatocellular carcinoma (HCC)) and non-cirrhotic (endocrine tumours (NETs)) livers. METHODS: In consecutive patients treated for a well-differentiated metastatic NET (n=120) or a HCC (n=88), 684 CT- and MR-scans were analysed. Liver/biliary injuries were classified as follows: dilated bile duct, portal vein narrowing, portal venous thrombosis and biloma/liver infarct. A generalised estimating equation logistic regression model was used. RESULTS: A liver/biliary injury followed 17.2% (82/476) of sessions in 30.8% (64/208) of patients. The occurrence of liver/biliary injury was associated with DEB-TACE (OR=6.63; p<0.001) irrespectively of the tumour type. Biloma/parenchymal infarct was strongly associated with both DEB-TACE (OR=9.78; p=0.002) and NETs (OR: 8.13; p=0.04). Biloma/liver infarcts were managed conservatively but were associated with an increase in serum levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatases, and gamma glutamyl transpeptidase (p=0.005, p=0.005, p=0.012, and p=0.006, respectively). CONCLUSIONS: Liver/biliary injuries are independently associated with DEB-TACE. Biloma/liver infarct, the most serious injury, is independently associated with both DEB-TACE and NETs. The absence of such an association in TACE of HCC may be explained by the hypertrophied peribiliary plexus observed in cirrhosis, which protects against the ischemic/chemical insult of bile ducts. We suggest caution when using DEB-TACE in the non-cirrhotic liver.

Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial.

PURPOSE: After curative resection, the prognosis of gastroesophageal adenocarcinoma is poor. This phase III trial was designed to evaluate the benefit in overall survival (OS) of perioperative fluorouracil plus cisplatin in resectable gastroesophageal adenocarcinoma. PATIENTS AND METHODS: Overall, 224 patients with resectable adenocarcinoma of the lower esophagus, gastroesophageal junction (GEJ), or stomach were randomly assigned to either perioperative chemotherapy and surgery (CS group; n = 113) or surgery alone (S group; n = 111). Chemotherapy consisted of two or three preoperative cycles of intravenous cisplatin (100 mg/m(2)) on day 1, and a continuous intravenous infusion of fluorouracil (800 mg/m(2)/d) for 5 consecutive days (days 1 to 5) every 28 days and three or four postoperative cycles of the same regimen. The primary end point was OS. RESULTS: Compared with the S group, the CS group had a better OS (5-year rate 38% v 24%; hazard ratio [HR] for death: 0.69; 95% CI, 0.50 to 0.95; P = .02); and a better disease-free survival (5-year rate: 34% v 19%; HR, 0.65; 95% CI, 0.48 to 0.89; P = .003). In the multivariable analysis, the favorable prognostic factors for survival were perioperative chemotherapy (P = .01) and stomach tumor localization (P < .01). Perioperative chemotherapy significantly improved the curative resection rate (84% v 73%; P = .04). Grade 3 to 4 toxicity occurred in 38% of CS patients (mainly neutropenia) but postoperative morbidity was similar in the two groups. CONCLUSION: In patients with resectable adenocarcinoma of the lower esophagus, GEJ, or stomach, perioperative chemotherapy using fluorouracil plus cisplatin significantly increased the curative resection rate, disease-free survival, and OS.

Prolonged survival of initially unresectable hepatic colorectal cancer patients treated with hepatic arterial infusion of oxaliplatin followed by radical surgery of metastases.

PURPOSE: The aim of this study was to analyze the impact of hepatic arterial infusion (HAI) of oxaliplatin with systemic 5-Fluorouracil and leucovorin on patients with isolated unresectable liver metastases. PATIENTS AND METHODS: A total of 87 patients treated in our hospital with HAI of oxaliplatin with systemic 5-Fluorouracil and leucovorin for isolated unresectable colorectal liver metastases from May 1999 to May 2007 were extracted from a prospective database and analyzed. The resectability rate, perioperative findings, postoperative outcomes, and long-term follow-up were evaluated. RESULTS: HAI was delivered after failure of previous systemic chemotherapy in 69 patients (79%). The main criterion for unresectability was massive liver involvement (86% of patients). Most patients had synchronous (85%), bilateral metastases (89%). The median number of HAI courses was 8 (0-25). About 31 patients experienced technical catheter-related problems, which were responsible for withdrawal of HAI in only 7 patients (8%). Finally, a total of 23 patients (26%) were operated on, and resection or radiofrequency ablation was performed in 21 patients (24%). No postoperative mortality was observed and the morbidity rate was 35%. Five-year overall survival was 56% in the surgery group versus none in the nonsurgery group (P < 0.0001). After a median follow-up of 63 months, intrahepatic recurrence occurred in 10 patients among the 23 operated patients. CONCLUSIONS: HAI of oxaliplatin with systemic 5-Fluorouracil and leucovorin offers a second chance to remove initially unresectable isolated colorectal liver metastases in 24% of patients, and appears to be more efficient when performed as first-line therapy. Long-term overall survival can be obtained with this approach.

The long-term impact of hyperthermic intraperitoneal chemotherapy on survivors treated for peritoneal carcinomatosis: a cross-sectional study.

BACKGROUND: Hyperthermic intraperitoneal chemotherapy (HIPEC) after complete surgical resection is currently accepted as a therapeutic option for peritoneal carcinomatosis. However, considerable morbidity is reported after HIPEC. OBJECTIVE: We aimed to evaluate the impact of HIPEC on the quality of life (QoL) of survivors without recurrences of disease according to socio-demographic and medical variables. For that purpose, HIPEC was used as a global concept including the surgical procedure effects. MATERIALS AND METHODS: A cross-sectional study was performed by analyzing questionnaires concerning socio-demographic data, the psychological status, and general and specific QoL scores. RESULTS: Sixty-eight patients (86% of those contacted) completed and returned mailed questionnaires. For 19/21 QoL dimensions explored, survivors reported good to very good QoL with a median score >/=67%. The two adversely affected dimensions were future prospects and sexual functioning with a mean score of 57% and 23%, respectively. The burden of carcinomatosis, evaluated by a peritoneal index, was not correlated with statistically identified sequels in QoL. The extent of morbidity due to HIPEC, evaluated by the hospital stay, was statistically correlated with only one score, namely, embarrassment during social activities (p = 0.01) but not during familial life. CONCLUSIONS: Even though HIPEC is considered as an aggressive treatment, survivors reported good to very good QoL. However, specific care for the psychological aspect, as reflected by anxiety regarding future prospects and sexual activity, needs to be developed for survivors.

High-dose irinotecan plus LV5FU2 or simplified LV5FU (HD-FOLFIRI) for patients with untreated metastatic colorectal cancer: a new way to allow resection of liver metastases?

UNLABELLED: The antitumor efficacy of irinotecan may be dose dependent. This study aimed to determine the safety and efficacy of high-dose (HD) irinotecan combined with LV5FU2 or simplified LV5FU (LV5FUs) in first-line treatment of metastatic colorectal cancer. PATIENTS AND METHODS: Patients with unresectable and measurable metastatic colorectal cancer, not pretreated for metastatic disease, were given irinotecan 260 mg/m(2) combined with LV5FU2 in the first 25 patients, then with LV5FUs (HD-FOLFIRI) in 35 patients. G-CSF was given in case of febrile neutropenia, grade 4 neutropenia >7 days or neutropenia grade >1 at day 15. RESULTS: The response rate was 57% (95% confidence interval 43-69%). Second surgery with curative intent was performed in 28% of patients, leading to 20% radiological complete response. Median response duration, time to progression and overall survival were 11, 9 and 22 months, respectively. The median dose intensity of irinotecan was 117 mg/m(2)/week. G-CSF was given to 45% of patients over 33% of cycles. Usual toxicity of irinotecan and 5-FU were observed without major increased frequency, except hematological toxicity. Tolerance was similar with LV5FU2 and LV5FUs, though more asymptomatic grade 3-4 neutropenia was observed with LV5FU2. CONCLUSION: HD-irinotecan plus LV5FU2 or HD-FOLFIRI is feasible and achieved a high response rate and postsurgery complete response rate.