Motor disorders related to oxaliplatin-induced peripheral neuropathy: long-term severity and impact on quality of life.

PURPOSE: Sensory chemotherapy-induced peripheral neuropathy (CIPN) is well-recognized, but motor CIPN remains understudied. This secondary analysis focused on the long-term severity and impact of motor disorders, their relation to sensory CIPN, neuropathic pain, psychological distress, and health-related quality of life (HRQoL) after oxaliplatin-based chemotherapy in colorectal cancer (CRC) survivors. METHODS: Data from a multicenter, cross-sectional study were re-analyzed to explore motor CIPN among CRC survivors up to 5 years post-chemotherapy, with no longitudinal follow-up. Questionnaires assessed sensory and motor CIPN (QLQ-CIPN20), neuropathic pain (DN4), anxiety and depression (HADS), and HRQoL (QLQ-C30). RESULTS: Among 405 CRC survivors, 31.1% had sensory CIPN as previously described. When categorizing the 405 CRC survivors based on the years since their last oxaliplatin-based chemotherapy, the motor scores derived from the QLQ-CIPN20 showed no significant difference between years (p = 0.08). Motor CIPN scores correlated with female gender, higher oxaliplatin dose intensity, sensory CIPN, and neuropathic pain. Motor CIPN also linked to decreased HRQoL and increased psychological distress. CONCLUSION: The study underscores the detrimental impact of motor disorders on CRC survivors post-oxaliplatin-based chemotherapy. Oncologists should prioritize assessing and managing motor manifestations alongside sensory symptoms to enhance post-cancer quality of life. TRIAL REGISTRATION: NCT02970526 (2016-11-22). https://classic. CLINICALTRIALS: gov/ct2/show/NCT02970526?term=NCT02970526&draw=2&rank=1 .

FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer.

BACKGROUND: Among patients with metastatic pancreatic cancer, combination chemotherapy with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) leads to longer overall survival than gemcitabine therapy. We compared the efficacy and safety of a modified FOLFIRINOX regimen with gemcitabine as adjuvant therapy in patients with resected pancreatic cancer. METHODS: We randomly assigned 493 patients with resected pancreatic ductal adenocarcinoma to receive a modified FOLFIRINOX regimen (oxaliplatin [85 mg per square meter of body-surface area], irinotecan [180 mg per square meter, reduced to 150 mg per square meter after a protocol-specified safety analysis], leucovorin [400 mg per square meter], and fluorouracil [2400 mg per square meter] every 2 weeks) or gemcitabine (1000 mg per square meter on days 1, 8, and 15 every 4 weeks) for 24 weeks. The primary end point was disease-free survival. Secondary end points included overall survival and safety. RESULTS: At a median follow-up of 33.6 months, the median disease-free survival was 21.6 months in the modified-FOLFIRINOX group and 12.8 months in the gemcitabine group (stratified hazard ratio for cancer-related event, second cancer, or death, 0.58; 95% confidence interval [CI], 0.46 to 0.73; P<0.001). The disease-free survival rate at 3 years was 39.7% in the modified-FOLFIRINOX group and 21.4% in the gemcitabine group. The median overall survival was 54.4 months in the modified-FOLFIRINOX group and 35.0 months in the gemcitabine group (stratified hazard ratio for death, 0.64; 95% CI, 0.48 to 0.86; P=0.003). The overall survival rate at 3 years was 63.4% in the modified-FOLFIRINOX group and 48.6% in the gemcitabine group. Adverse events of grade 3 or 4 occurred in 75.9% of the patients in the modified-FOLFIRINOX group and in 52.9% of those in the gemcitabine group. One patient in the gemcitabine group died from toxic effects (interstitial pneumonitis). CONCLUSIONS: Adjuvant therapy with a modified FOLFIRINOX regimen led to significantly longer survival than gemcitabine among patients with resected pancreatic cancer, at the expense of a higher incidence of toxic effects. (Funded by R&D Unicancer and others; ClinicalTrials.gov number, NCT01526135 ; EudraCT number, 2011-002026-52 .).

Longitudinal analysis of health-related quality of life in cancer clinical trials: methods and interpretation of results.

PURPOSE: Health-related quality of life (HRQoL) is assessed by self-administered questionnaires throughout the care process. Classically, two longitudinal statistical approaches were mainly used to study HRQoL: linear mixed models (LMM) or time-to-event models for time to deterioration/time until definitive deterioration (TTD/TUDD). Recently, an alternative strategy based on generalized linear mixed models for categorical data has also been proposed: the longitudinal partial credit model (LPCM). The objective of this article is to evaluate these methods and to propose recommendations to standardize longitudinal analysis of HRQoL data in cancer clinical trials. METHODS: The three methods are first described and compared through statistical, methodological, and practical arguments, then applied on real HRQoL data from clinical cancer trials or published prospective databases. In total, seven French studies from a collaborating group were selected with longitudinal collection of QLQ-C30. Longitudinal analyses were performed with the three approaches using SAS, Stata and R software. RESULTS: We observed concordant results between LMM and LPCM. However, discordant results were observed when we considered the TTD/TUDD approach compared to the two previous methods. According to methodological and practical arguments discussed, the approaches seem to provide additional information and complementary interpretations. LMM and LPCM are the most powerful methods on simulated data, while the TTD/TUDD approach gives more clinically understandable results. Finally, for single-item scales, LPCM is more appropriate. CONCLUSION: These results pledge for the recommendation to use of both the LMM and TTD/TUDD longitudinal methods, except for single-item scales, establishing them as the consensual methods for publications reporting HRQoL.

Fong's Score in the Era of Modern Perioperative Chemotherapy for Metastatic Colorectal Cancer: A Post Hoc Analysis of the GERCOR-MIROX Phase III Trial.

BACKGROUND: Despite improvement in colorectal liver metastasis (CLM) treatment, survival after liver surgery remains highly variable. Several clinicopathologic prognostic factors have been reported, but their validity in the era of more effective perioperative chemotherapy remains to be defined. The aim of this study is to analyze the prognostic factors associated with survival after CLM resection. METHODS: Clinicopathologic data of patients included in the MIROX phase III trial who underwent surgery for isolated CLMs were analyzed. The primary endpoints were 5-year overall survival (OS) and disease-free survival (DFS). Univariate Cox analysis was performed to identify associations with OS and DFS and select variables for inclusion in a multivariate model to determine their independent prognostic value. RESULTS: A total of 181 patients were analyzed. The median follow-up period was 6.42 years [95% confidence interval (CI) 5.15-8.71 years], and the 5-year OS and DFS rates were 67.1% and 35.4%, respectively. On multivariate analysis, Fong's clinical risk score (CRS) as a categorical variable (CRS 0-1 vs. 2-3 vs. 4-5, p = 0.036) and polymorphonuclear neutrophil (PMN) count (> 6000/mm3 vs. ≤ 6000/mm3, p = 0.006) before chemotherapy were found to be independent prognostic factors for OS. However, only Fong's CRS remained significantly associated with DFS (p = 0.027). The final OS model was used to establish a nomogram that allows individual OS estimations at 1, 3, 5, and 10 years. CONCLUSIONS: Fong's CRS was independently associated with DFS and poor OS after CLM resection with FOLFOX-based chemotherapy regimen. It could be useful in daily practice and future trials to select patients more accurately.

Laparoscopic Partial ALPPS: Much Better Than ALPPS!

Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS) has emerged as an alternative for patients with bilobar colorectal liver metastasis deemed unresectable due to inadequate future remnant liver (FRL). Nevertheless, high morbidity and mortality rates have been reported. In this setting, including hepatobiliary scintigraphy in the clinical and surgical management of patients offered ALPPS has been advocated to both assess eligibility for ALPPS stagel and suitable time for ALPPS stage2. Recently, it was stated that partial ALPPS with a liver split restricted to 50% of the transection line (or up to the middle hepatic vein in case of right extended hepatectomy) and a shortened stagel allows improving the postoperative course without precluding the inter-stages FRL hypertrophy. We describe a case series of p-ALPPS with stagel performed laparoscopically, including sequential assessments of the FRL volumes and functions via pre-stagel and pre-stage2 computed tomography volumetry and HIDA SPECT-scintigraphy. In five patients, laparoscopic p-ALPPS was associated with rapid and significant gain of remnant functional volume - much better than previously observed for ALPPS - facilitating early stage2 without inflammatory adherences. In conclusion, laparoscopic p-ALPPS is feasible and seems less aggressive than the original ALPPS technique with total transection. It may be an interesting alternative to the classical portal vein embolization (PVE) and two-stage hepatectomy strategy.

Repeated Resections of Hepatic and Pulmonary Metastases from Colorectal Cancer Provide Long-Term Survival.

BACKGROUND: Liver and lungs are the two most frequent sites of metastatic spread of colorectal cancer (CRC). Complete resection of liver and/or lung metastases is the only chance of cure, and several studies have reported an improved survival after an aggressive treatment. Nevertheless, CRC liver metastases (CLM) have been recognized as a pejorative factor for patients undergoing pulmonary metastasectomy. We report our experience with patients successively operated on for CRC hepatic and pulmonary metastasis (CPM) and seek to identify prognostic factors. METHODS: All consecutive patients who had resection of CPM and CLM between 2001 and 2014 were enrolled in the study. Clinicopathological and survival data were retrospectively analysed. RESULTS: Forty-six patients underwent resections of both CLM and CPM. Hepatic resection preceded pulmonary resection in most cases (91.3%). The median intervals between the resection of the primary tumour and the hepatic recurrence and between hepatic and pulmonary recurrences were 12 months [0-72] and 21.5 months [1-84], respectively. The mortality rate following CPM resection was 4.3%. After a median follow-up of 41.5 months [0-126], 35 patients recurred of whom 14 (40%) and 11(31.4%) could benefit from repeated resection of recurrent CLM and CPM, respectively. The median and 5-year overall survivals (OS) were 53 months and 49%, respectively. No prognostic factor was identified. CONCLUSION: An aggressive management of CLM and CPM, including repeated resections, may provide a long-term survival comparable to survival of patients with unique metastasectomy. The absence of prognostic factor may reflect the highly selected pattern of the eligible patients.

Copy number variations in DCC/18q and ERBB2/17q are associated with disease-free survival in microsatellite stable colon cancer.

We conducted a prospective study to assess the prognostic impact of selected copy number variations (CNVs) in Stage II-III microsatellite stable (MSS) colon cancer. A total of 401 patients were included from 01/2004 to 01/2009. The CNVs in 8 selected target genes, DCC/18q, EGFR/7p, TP53/17p, BLK/8p, MYC/8q, APC/5q, ERBB2/17q and STK6/20q, were detected using a quantitative multiplex polymerase chain reaction of short fluorescent fragment (QMPSF) method. The primary end-point was the impact of the CNVs on the 4-year disease-free survival (DFS). The recurrence rate at 4 years was 20.9%, corresponding to 14% Stage II patients versus 31% Stage III patients (p < 0.0001). The 4-year DFS was significantly decreased in patients with a loss at DCC/18q (p = 0.012) and a gain at ERBB2/17q (p = 0.041). The multivariate analysis demonstrated that Stage III, a loss at DCC/18q and a gain at ERBB2/17q were independent factors associated with DFS. A combination of DCC/18q and ERBB2/17q was also associated with relapse, with the hazard ratio increasing from 1 to 2.4 (95% confidence interval (CI), 1.5-4.1) and 3.1 (95% CI, 1.2-8.4) in the presence of 0, 1 or 2 alterations, respectively (p = 0.0013). CNVs in DCC/18q and ERBB2/17q are significantly associated with DFS in Stage II-III MSS colon cancer.

Pharmacogenetic determinants of outcomes on triplet hepatic artery infusion and intravenous cetuximab for liver metastases from colorectal cancer (European trial OPTILIV, NCT00852228).

BACKGROUND: The hepatic artery infusion (HAI) of irinotecan, oxaliplatin and 5-fluorouracil with intravenous cetuximab achieved outstanding efficacy in previously treated patients with initially unresectable liver metastases from colorectal cancer. This planned study aimed at the identification of pharmacogenetic predictors of outcomes. METHODS: Circulating mononuclear cells were analysed for 207 single-nucleotide polymorphisms (SNPs) from 34 pharmacology genes. Single-nucleotide polymorphisms passing stringent Hardy-Weinberg equilibrium test were tested for their association with outcomes in 52 patients (male/female, 36/16; WHO PS, 0-1). RESULTS: VKORC1 SNPs (rs9923231 and rs9934438) were associated with early and objective responses, and survival. For rs9923231, T/T achieved more early responses than C/T (50% vs 5%, P=0.029) and greatest 4-year survival (46% vs 0%, P=0.006). N-acetyltransferase-2 (rs1041983 and rs1801280) were associated with up to seven-fold more macroscopically complete hepatectomies. Progression-free survival was largest in ABCB1 rs1045642 T/T (P=0.026) and rs2032582 T/T (P=0.035). Associations were found between toxicities and gene variants (P<0.05), including neutropenia with ABCB1 (rs1045642) and SLC0B3 (rs4149117 and rs7311358); and diarrhoea with CYP2C9 (rs1057910), CYP2C19 (rs3758581), UGT1A6 (rs4124874) and SLC22A1 (rs72552763). CONCLUSION: VKORC1, NAT2 and ABCB1 variants predicted for HAI efficacy. Pharmacogenetics could guide the personalisation of liver-targeted medico-surgical therapies.

Factors associated with fatal liver failure after extended hepatectomy.

BACKGROUND: Posthepatectomy liver failure (PHLF) is the leading cause of posthepatectomy mortality. This study aimed to revisit the etiology and pattern of PHLF and its role in posthepatectomy morbidity and mortality. METHODS: The pattern and etiology of PHLF and subsequent morbidity and mortality were analysed in the subgroup of patients without cirrhosis undergoing an extended hepatectomy (≥4 segments) over a 5 year period. PHLF was defined using ISGLS criteria and/or 50-50 and/or peak serum bilirubin >7 mg/dl. RESULTS: Among 285 included patients (median age 62 [20-89]), 81 (28%) developed PHLF with higher rates of major complications (38%) and mortality (27%) than patients without PHLF (13% and 2%, respectively; p < 0.001). Twenty-six patients (9%) died, 22 of whom had PHLF. Of these 22 patients, only 4 patients died from complications purely-attributed to PHLF. All the remaining 18 patients had additional peri-operative factors that contributed to the mortality of which severe vascular events were the most common. CONCLUSION: PHLF is associated with higher rates of morbidity and mortality following extended resection. The etiology of PHLF is multifactorial with vascular events being common precipitant. The multifactorial origin of PHLF may explain the low predictive value of current clinical risk scores.

Overexpression of chemokine receptor CXCR2 and ligand CXCL7 in liver metastases from colon cancer is correlated to shorter disease-free and overall survival.

Our aim was to analyze the potential role of chemokine receptors CXCR2 and CXCR4 signalling pathways in liver metastatic colorectal cancer (CRC) relapse. CXCR2, CXCR4, and their chemokine ligands were evaluated in liver metastases of colorectal cancer in order to study their correlation with overall and disease-free survival of patients having received, or not received, a neoadjuvant chemotherapy regimen. Quantitative RT-PCR and CXCR2 immunohistochemical staining were carried out using CRC liver metastasis samples. Expression levels of CXCR2, CXCR4, and their ligands were statistically analyzed according to treatment with neoadjuvant chemotherapy and patients' outcome. CXCR2 and CXCL7 overexpression are correlated to shorter overall and disease-free survival. By multivariate analysis, CXCR2 and CXCL7 expressions are independent factors of overall and disease-free survival. Neoadjuvant chemotherapy increases significantly the expression of CXCR2: treated group 1.89 (0.02-50.92) vs 0.55 (0.07-3.22), P = 0.016. CXCL7 was overexpressed close to significance, 0.40 (0.00-7.85) vs 0.15 (0.01-7.88), P = 0.12. We show the involvement of CXCL7/CXCR2 signalling pathways as a predictive factor of poor outcome in metastatic CRC. 5-Fluorouracil-based chemotherapy regimens increase the expression of these genes in liver metastasis, providing one explanation for aggressiveness of relapsed drug-resistant tumors. Selective blockage of CXCR2/CXCL7 signalling pathways could provide new potential therapeutic opportunities.

Liver function following extended hepatectomy can be accurately predicted using remnant liver volume to body weight ratio.

BACKGROUND: Standardised measurement of remnant liver volume (RLV), where total liver volume (TLV) is calculated from patients' body surface area (RLV-sTLV), has been advocated. Extrapolating the model of living donor liver transplantation, we showed in a pilot study that the simplified RLV/body weight ratio (RLVBWR) was accurate in assessing the functional limit of hepatectomy. The aim of the study was to compare in a prospective series of extended right hepatectomy the predictive value of the RLVBWR and the RLV-sTLV at a cut-off of 0.5% (RLVBWR0.5%) and 20% (RLV-sTLV20%), respectively. METHODS: We studied the impact of RLVBWR0.5% and of RLV-sTLV20% on three months morbidity and mortality in 74 non-cirrhotic patients operated on for malignant tumours. Of these, 47 patients who were not included in the initial pilot study were enrolled in a prospective validation cohort to reappraise the predictive value of each method. RESULTS: RLVBWR and RLV-sTLV were highly correlated (Pearson correlation coefficient, 0.966). Three months overall and severe morbidity (grade 3b-5) and mortality were significantly increased in groups RLVBWR ≤ 0.5% and RLV-sTLVs ≤ 20% compared to groups >0.5% and >20%, respectively. The sensitivity and specificity in predicting death from liver failure were 100 and 84.1% for RLVBWR0.5% and 60 and 94.2% for RLV-sTLV20%, respectively. Similar results were observed in the validation cohort for the RLVBWR0.5% (lack of statistical power for RLV-sTLV as only 2 patients showed a RLV-sTLV ≤ 20%). CONCLUSIONS: The RLVBWR0.5% is a method of assessing the remnant liver that is simple and as reliable as the standardised RLV-sTLV20%.

Tumour biology of colorectal liver metastasis is a more important factor in survival than surgical margin clearance in the era of modern chemotherapy regimens.

BACKGROUND: The aim of the authors was to reassess the impact of a positive surgical margin (R1) after a liver resection for colorectal liver metastases (CLMs) on survival in the era of modern chemotherapy, through their own experience and a literature review. METHODS: Inclusion criteria were: R1 or R0 resection with no local treatment modalities, extra-hepatic metastases or other cancer. RESULTS: Among 337 patients operated between 2000 and 2010, 273 patients were eligible (214 R0/59 R1). The mean follow-up was 43 ± 29 months. Compared with a R0 resection, a R1 resection offered a lower 5-year overall (39.1% versus 54.2%, P = 0.010), disease-free (15.2% versus 31.1%, P = 0.021) and progression-free (i.e. time to the first non-curable recurrence; 33.1% versus 47.3%, P = 0.033) survival rates. Metastases in the R1 group were more numerous, larger and more frequently synchronous. Independent factors of poor survival were: number, size and short-time interval of CLM occurrence, N status, rectal primary, absence of adjuvant chemotherapy, but not a R1 resection. With the more-systematic administration of chemotherapy since 2005, the intergroup difference in progression-free survival disappeared (P = 0.264). CONCLUSION: A R1 resection had no prognostic value per se but reflected a more severe disease. The recent change in the prognostic value of a R1 resection may be linked to the beneficial effect of chemotherapy.

Relevance of the ISGLS definition of posthepatectomy liver failure in early prediction of poor outcome after liver resection: study on 680 hepatectomies.

OBJECTIVE: To assess the relevance of the International Study Group of Liver Surgery (ISGLS) definition of posthepatectomy liver failure compared with 2 well-established criteria, 50-50 and PeakBili>7, as early predictors of posthepatectomy outcome. BACKGROUND: There is limited data on the postoperative use of ISGLS definition of posthepatectomy liver failure as early predictor of outcome. METHODS: Between 2007 and 2012, a total of 680 hepatectomies were analyzed from a prospective database. The value of each definition for prediction of 3-month major complications (Clavien III-V) and mortality was assessed either within 10 days of surgery or on postoperative day 5. RESULTS: Three-month major morbidity and mortality rates were 16.5% and 4.4%, respectively. Within 10 days, 79 patients fulfilled ISGLS definition compared with 24 for 50-50 and 44 for PeakBili>7 criteria. Sensitivities of ISGLS definition and 50-50 and PeakBili>7 criteria for prediction of major morbidity and mortality were 35.8, 17.4, 24.8% and 56.7, 36.7, 56.7%, respectively. Patients with no positive score had a risk of death or major complication below 5% and 15%, respectively. In patients with a positive score, the ISGLS definition was the least relevant to predict major complications and mortality (positive predictive values of 49.4% and 21.8% vs 79.2% and 47.8% for 50-50 and 61.4% and 40.5% for PeakBili>7 criteria). The relative risk of death was 6.9 (95% confidence interval, 3.1-15.4) if the ISGLS definition was evaluated on postoperative day 5 versus 21.1 (95% confidence interval, 7.7-57.7) for 50-50 and 21.7 (95% confidence interval, 7.4-63.3) for PeakBili>7 criteria. CONCLUSIONS: ISGLS definition was less discriminatory than 50-50 and PeakBili>7 criteria in identifying patients at risk of posthepatectomy major complications or death.

Gemcitabine plus oxaliplatin in advanced hepatocellular carcinoma: a large multicenter AGEO study.

BACKGROUND & AIMS: The current standard treatment for advanced hepatocellular carcinoma (HCC) is sorafenib. This drug is effective but generally does not induce tumor shrinkage and other treatment options are still needed. METHODS: This retrospective multicenter study included all consecutive patients with advanced HCC treated with gemcitabine and oxaliplatin (GEMOX) between 2001 and 2010. Survival curves were drawn with the Kaplan-Meier method and compared with the log-rank test. Univariate and multivariate analyses were used to evaluate prognostic factors. RESULTS: Two hundred four consecutive patients were treated with GEMOX (median age, 60 years; men, 86%; underlying cirrhosis, 76%). Grade 3-4 toxicity was observed in 44% of the patients (thrombocytopenia 24%, neutropenia 18%, diarrhea 14%, neurotoxicity 12%) leading to treatment discontinuation in 16% of the cases. The overall response and disease control rates were 22% (95% CI, 16-27) and 66% (95% CI, 59-72), respectively. No clinical or biological factors were associated with the treatment response, and 8.5% of the patients were subsequently eligible for curative-intent therapies after downstaging. Median PFS, TTP, and OS were 4.5 (95% CI, 4-6), 8 (95% CI, 6-11), and 11 months (95% CI, 9-14), respectively. In multivariate analysis, gender (p=0.03), underlying cirrhosis (p=0.01), CLIP score (p=0.03), and response to GEMOX (p<0.0001) were independently associated with OS. CONCLUSIONS: This large study confirms that GEMOX is effective with manageable toxicity in patients with advanced HCC. Tumor responses permitted potentially curative treatment that was not initially feasible in a significant proportion of patients.

Volumetric gain of the liver after major hepatectomy in obese patients: a case-matched study in 84 patients.

OBJECTIVE: The objective was to determine the liver volumetric recovering capacity and postoperative course after major hepatectomy in obese patients through a case-matched study. BACKGROUND: In literature, the impact of obesity on liver recovering has been analyzed only indirectly in terms of morbimortality but never through volumetric assessment. PATIENTS AND METHOD: Between 2005 and 2011, 42 patients with body mass index (BMI) 30 or higher (Ob group) underwent major hepatectomy and were matched with 42 patients with BMI 25 or lower (NonOb group) on the magnitude of resection (number of resected segments ±1, remnant liver volume to total liver volume, RLV/TLV, ±5%). The RLV was measured on computed tomographic slices preoperatively and postoperatively at 1 month (RLV-1M) for all patients and within 3 to 12 months in 42 paired patients (median = 6 months, RLV-6M). Considering hepatomegaly in Ob group, RLV was also normalized to body weight (RLVBWR). The liver volumetric gain was expressed as a relative increase [(RLV-1M - RLV)/RLV] or increase in RLVBWR. RESULTS: The Ob and NonOb groups were comparable regarding clinicopathological data, except for arterial hypertension (48% vs 19%; P = 0.005), mean steatosis (24% vs 10%; P = 0.03), and fibrosis incidence (33% vs 10%; P = 0.008). Ob group showed longer operative time and higher blood losses. There were no intergroup differences in liver failure (both 7.1%) and 90-day morbimortality. Despite comparable RLV/TLV (38.1% vs 37.7%; P = 0.13), the relative liver volumetric gain at 1 month was significantly lower in Ob group (+93% vs +115%; P = 0.002), as well as RLVBWR increase (+0.59% vs +0.79%; P < 0.001). The RLV-1M represented 66.2% of initial TLV in Ob group compared with 73.8% (P = 0.005) in NonOb group. This delay in relative volumetric gain persisted at 6 months (+105.4% vs +137.6%; P = 0.009), the RLV-6M representing 71.2% vs 82.4% of initial TLV (P = 0.014). CONCLUSIONS: In a methodologically robust trial in the first cohort reported up to date, the regenerative response in obese patients was comparatively slower based on their initial TLV or body weight.

Volumetric analysis of remnant liver regeneration after major hepatectomy in bevacizumab-treated patients: a case-matched study in 82 patients.

BACKGROUND: The objective was to determine the liver regeneration capacity and morbidity and mortality rates after major hepatectomy for colorectal metastases in patients having undergone bevacizumab-based chemotherapy (bev+). PATIENTS AND METHODS: Between 2006 and 2011, 41 patients underwent major hepatectomy within 3 months of bevacizumab and were matched with 41 patients operated on following systemic chemotherapy without bevacizumab (bev-). The matching criteria were the following: number of courses of chemotherapy, chemotherapy-free interval, age, and type of hepatectomy. After measurements of remnant liver volume (RLV) preoperatively and at 1 month (RLV1M), volumetric gain was calculated as absolute (RLV1M-RLV) or relative regeneration [(RLV1M-RLV/RLV)]. Ninety-day morbidity was rated according to the Clavien-Dindo classification. RESULTS: There were 21 right, 9 extended right, and 11 left hepatectomies in each group. Groups were comparable in terms of matching criteria, body mass index, American Society of Anesthesiologists score, and RLV. No mortalities were observed. There were no intergroup differences in overall morbidity (56% in bev+ vs 34.1%; P = 0.075) or postoperative liver failure. A severe complication occurred in 5 bev+ (4 eviscerations) and 4 bev- (bile leakages) (P = 0.95). The median hospital stay was similar in both groups as were the degrees of absolute and relative liver regeneration (143% in bev+ vs 114%; P = 0.20). Liver regeneration was not influenced by the type of hepatectomy, the number of courses of chemotherapy, or age more than 65 years. CONCLUSIONS: In a methodologically robust trial in the largest cohort reported up to date, bevacizumab did not impair liver regeneration after major hepatectomy-even in elderly patients or those with high exposure to chemotherapy.

Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX-6) as first-line treatment for metastatic colorectal cancer.

A regimen consisting of 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX-6) is widely used in France in the first-line treatment of metastatic colorectal cancer (MCRC). The aim of our study was to demonstrate the non-inferiority of capecitabine plus oxaliplatin (XELOX) versus FOLFOX-6 for this indication. Patients were randomly assigned to receive XELOX or FOLFOX-6 for 6 months. The primary endpoint was overall response rate (ORR) in the per-protocol (PP) population; however, progression-free and overall survival (OS), time to response and response duration were also assessed. A total of 306 patients were enrolled (XELOX n = 156; FOLFOX-6 n = 150). ORR was 42 and 46% with XELOX and FOLFOX-6, respectively, in the PP population. The difference between groups was 4.7%; the upper limit of the unilateral 95% confidence interval (14.4%) was below the non-inferiority margin of 15%. In the intent-to-treat population, median progression-free survival was 8.8 months with XELOX and 9.3 months with FOLFOX-6, and median OS was 19.9 and 20.5 months, respectively. XELOX patients had significantly more grade 3/4 thrombocytopenia (12% vs. 5%) and diarrhoea (14% vs. 7%), but significantly less grade 3/4 neutropenia (5% vs. 47%), febrile neutropenia (0% vs. 6%) and neuropathy (11% vs. 26%) than FOLFOX-6 patients. We conclude that XELOX is non-inferior in terms of efficacy to FOLFOX-6 in the first-line treatment of MCRC, but has a different toxicity profile.