Stéphanie Laurent

Value of DCE-MRI and FDG-PET/CT in the prediction of response to preoperative chemotherapy with bevacizumab for colorectal liver metastases

Background:The purpose of this study was to assess the role of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and 18F-fluorodeoxyglucose positron emission tomography computed tomography (FDG-PET/CT) for evaluation of response to chemotherapy and bevacizumab and for prediction of progression-free survival (PFS) in patients with metastatic colorectal cancer (mCRC) with potentially resectable liver lesions.Methods:A total of 19 mCRC patients were treated with FOLFOX/FOLFIRI and bevacizumab followed by surgery. Dynamic contrast-enhanced magnetic resonance imaging and FDG-PET/CT were performed before treatment and after cycle 5. PET results were quantified by calculating maximum standardised uptake value (SUVmax) whereas area under the enhancement curve (AUC), initial AUC (iAUC) and the endothelial transfer constant (Ktrans) were used to quantify DCE-MRI. Pathological analysis of the resection specimen was performed, including measurement of microvessel density (MVD) and proliferation index.Results:Both AUC and iAUC were significantly decreased following bevacizumab therapy (median change of 22% (P=0.002) and 40% (P=0.001) for AUC and iAUC, respectively). Progression-free survival benefit was shown for patients with >40% reduction in Ktrans (P=0.019). In the group of radiological responders, the median baseline SUVmax was 3.77 (IQR: 2.88–5.60) compared with 7.20 (IQR: 4.67–8.73) in nonresponders (P=0.021). A higher follow-up SUVmax was correlated with worse PFS (P=0.012). Median MVD was 10.9. Progression-free survival was significantly shorter in patients with an MVD greater than 10, compared with patients with lower MVD (10 months compared with 16 months, P=0.016).Conclusion:High relative decrease in Ktrans, low follow-up SUVmax and low MVD are favourable prognostic factors for mCRC patients treated with bevacizumab before surgery.

Adjuvant gemcitabine versus NEOadjuvant gemcitabine/oxaliplatin plus adjuvant gemcitabine in resectable pancreatic cancer: a randomized multicenter phase III study (NEOPAC study)

BackgroundDespite major improvements in the perioperative outcome of pancreas surgery, the prognosis of pancreatic cancer after curative resection remains poor. Adjuvant chemotherapy increases disease-free and overall survival, but this treatment cannot be offered to a significant proportion of patients due to the surgical morbidity. In contrast, almost all patients can receive (neo)adjuvant chemotherapy before surgery. This treatment is safe and effective, and has resulted in a median survival of 26.5 months in a recent phase II trial. Moreover, neoadjuvant chemotherapy improves the nutritional status of patients with pancreatic cancer. This multicenter phase III trial (NEOPAC) has been designed to explore the efficacy of neoadjuvant chemotherapy.Methods/DesignThis is a prospective randomized phase III trial. Patients with resectable cytologically proven adenocarcinoma of the pancreatic head are eligible for this study. All patients must be at least 18 years old and must provide written informed consent. An infiltration of the superior mesenteric vein > 180° or major visceral arteries are considered exclusion criteria. Eligible patients will be randomized to surgery followed by adjuvant gemcitabine (1000 mg/m2) for 6 months or neoadjuvant chemotherapy (gemcitabine 1000 mg/m2, oxaliplatin 100 mg/m2) followed by surgery and the same adjuvant treatment. Neoadjuvant chemotherapy is given four times every two weeks. The staging as well as the restaging protocol after neoadjuvant chemotherapy include computed tomography of chest and abdomen and diagnostic laparoscopy. The primary study endpoint is progression-free survival. According to the sample size calculation, 155 patients need to be randomized to each treatment arm. Disease recurrence will be documented by scheduled computed tomography scans 9, 12, 15, 21 and thereafter every 6 months until disease progression. For quality control, circumferential resection margins are marked intraoperatively, and representative histological sections will be centrally reviewed by a dedicated pathologist.DiscussionThe NEOPAC study will determine the efficacy of neoadjuvant chemotherapy in pancreatic cancer for the first time and offers a unique potential for translational research. Furthermore, this trial will provide the unbiased overall survival of all patients undergoing surgery for resectable cancer of the pancreatic head.Trial registrationclinicalTrials.gov NCT01314027

Laparoscopic liver resection compared to open approach in patients with colorectal liver metastases improves further resectability: Oncological outcomes of a case-control matched-pairs analysis

AIMS Liver resection is considered the standard treatment of colorectal metastases (CRLM). However, to date, no long term oncological results and data regarding repeat hepatectomy after laparoscopic approach are known. The aim of this study is to analyze single center long-term surgical and oncological outcomes after liver resection for CRLM. METHODS A total of 57 open resections (OR) were matched with 57 laparoscopic resections (LR) for CRLM. Matching was based mainly on number of metastases, tumor size, segmental position of lesions, type of hepatectomy and type of resection. RESULTS Morbidity rate was significantly less in the LR group (p = 0.002); the length of hospital stay was 6.5 ± 5 days for the LR group and 9.2 ± 4 days for the OR group (p = 0.005). After a median follow up of 53.7 months for the OR group and 40.9 months for the LR group, the 5-y overall survival rate was 65% and 60% respectively (p = 0.36) and the 5-y disease free survival rate was 38% and 29% respectively (p = 0.24). More patients in the LR group received a third hepatectomy for CRLM relapse than in the OR group (80% vs. 14.3% respectively; p = 0.015). CONCLUSIONS Laparoscopic resection for CRLM offers advantages in terms of reduced blood loss, morbidity rate and hospital stay. It provides comparable long-term oncological outcomes but can improve further resectability in patients with recurrent disease.

MDM2 gene amplification and protein expressions in colon carcinoma: is targeting MDM2 a new therapeutic option?

The aim of this study was to investigate murine double minute-2 (MDM2) gene copy number changes in colon carcinoma and to correlate these findings with an immunohistochemical analysis of MDM2 protein expression and histopathologic prognostic indicators of the tumors. The study included 80 cases of sporadic colon carcinomas. MDM2 protein expression was assessed by immunohistochemistry, and MDM2 gene status by fluorescence in situ hybridization. MDM2 gene amplification was detected in 18% of the 80 cases examined. A strong correlation was found between MDM2 gene amplification and the presence, intensity, and staining proportion of cytoplasmic MDM2 protein expression (p = 0.01). No correlation was found between MDM2 gene amplification and the well-established histopathologic prognostic factors. Given the correlation with gene amplification, we clearly demonstrated that cytoplasmic expression of MDM2 protein is true and relevant and that this finding has to be taken into account when immunohistochemistry would be used as a screening for MDM2 gene amplification in the near future. Targeting MDM2 could be a new approach in colon cancer therapy. The amplification status could be a predictive factor of the response to MDM2-targeted therapy.

Focus on 16p13.3 Locus in Colon Cancer

Background With one million new cases of colorectal cancer (CRC) diagnosed annually in the world, CRC is the third most commonly diagnosed cancer in the Western world. Patients with stage I-III CRC can be cured with surgery but are at risk for recurrence. Colorectal cancer is characterized by the presence of chromosomal deletions and gains. Large genomic profiling studies have however not been conducted in this disease. The number of a specific genetic aberration in a tumour sample could correlate with recurrence-free survival or overall survival, possibly leading to its use as biomarker for therapeutic decisions. At this point there are not sufficient markers for prediction of disease recurrence in colorectal cancer, which can be used in the clinic to discriminate between stage II patients who will benefit from adjuvant chemotherapy. For instance, the benefit of adjuvant chemotherapy has been most clearly demonstrated in stage III disease with an approximately 30 percent relative reduction in the risk of disease recurrence. The benefits of adjuvant chemotherapy in stage II disease are less certain, the risk for relapse is much smaller in the overall group and the specific patients at risk are hard to identify. Materials and Methods In this study, array-comparative genomic hybridization analysis (array-CGH) was applied to study high-resolution DNA copy number alterations in 93 colon carcinoma samples. These genomic data were combined with parameters like KRAS mutation status, microsatellite status and clinicopathological characteristics. Results Both large and small chromosomal losses and gains were identified in our sample cohort. Recurrent gains were found for chromosome 1q, 7, 8q, 13 and 20 and losses were mostly found for 1p, 4, 8p, 14, 15, 17p, 18, 21 and 22. Data analysis demonstrated that loss of chromosome 4 is linked to a worse prognosis in our patients series. Besides these alterations, two interesting small regions of overlap were identified, which could be associated with disease recurrence. Gain of the 16p13.3 locus (including the RNA binding protein, fox-1 homolog gene, RBFOX1) was linked with a worse recurrence-free survival in our patient cohort. On the other hand, loss of RBFOX1 was only found in patients without disease recurrence. Most interestingly, above mentioned characteristics were also found in stage II patients, for whom there is a high medical need for the identification of new prognostic biomarkers. Conclusions In conclusion, copy number variation of the 16p13.3 locus seems to be an important parameter for prediction of disease recurrence in colon cancer.

The subgroups of the phase III RECOURSE trial of trifluridine/tipiracil (TAS-102) versus placebo with best supportive care in patients with metastatic colorectal cancer

Background: In the phase III RECOURSE trial, trifluridine/tipiracil (TAS-102) extended overall survival (OS) and progression-free survival (PFS) with an acceptable toxicity profile in patients with metastatic colorectal cancer refractory or intolerant to standard therapies. The present analysis investigated the efficacy and safety of trifluridine/tipiracil in RECOURSE subgroups. Methods: Primary and key secondary end-points were evaluated using a Cox proportional hazards model in prespecified subgroups, including geographical subregion (United States of America [USA], European Union [EU], Japan), age (<65 years, ≥65 years) and v-Ki-ras2 Kirsten rat sarcoma 2 viral oncogene homologue (KRAS) status (wild type, mutant). Safety and tolerability were reported with descriptive statistics. Results: Eight-hundred patients were enrolled: USA, n = 99; EU, n = 403; Japan, n = 266. Patients aged ≥65 years and those with mutant KRAS tumours comprised 44% and 51% of all patients in the subregions, respectively. Final OS analysis (including 89% of events, compared with 72% in the initial analysis) confirmed the survival benefit associated with trifluridine/tipiracil, with a hazard ratio (HR) of 0.69 (95% confidence interval [CI] 0.59–0.81; P = 0.0001). Median OS in the three regions was 6.5–7.8 months in the trifluridine/tipiracil arm and 4.3–6.7 months in the placebo arm (USA: HR 0.56; 95% CI 0.34–0.94; P = 0.0277; EU: HR 0.62; 95% CI 0.48–0.80; P = 0.0002; Japan: HR 0.75; 95% CI 0.57–1.00; P = 0.0470). Median PFS was 2.0–2.8 months for trifluridine/tipiracil and 1.7–1.8 months for placebo; HRs favoured trifluridine/tipiracil in all regions. Similar clinical benefits of trifluridine/tipiracil were observed in elderly patients and in those with mutant KRAS tumours. There were no marked differences among subregions in terms of safety and tolerability. Conclusions: Trifluridine/tipiracil was effective in all subgroups, regardless of age, geographical origin or KRAS status. This trial is registered with ClinicalTrials.gov: NCT01607957.

Exploring limits for data registration in the context of PROCARE, a quality improvement project on rectal cancer.

Abstract Background : A high burden of registration in the context of quality improvement projects may result in registration fatigue. Methods : Time required for data collection and registration was measured. Quality of care indicators (QCI) were scored and factors for adjusted benchmarking were identified. The PROCARE data set was compared with 5 other European data sets. Results : Time required for data collection varied per domain while time for registration was more uniform. On average, per item 33 seconds were needed for collection and registration. The number of data to be registered per patient was 48276, depending on the stage of the disease, resulting in a minimum of 25 minutes and a maximum of 2 hours 4 minutes per patient, follow-up not included. Focusing on 43 clinically relevant QCIs would result in a 50% reduction, using aggregate scores for performance audit in a 71% reduction. The PROCARE data set was larger than comparable European data sets. Linkage of the PROCARE database with administrative databases provided confident data on the patients’ survival status, but did not appear to be a practical option for other QCIs. Conclusions : Limiting the aim to performance audit could significantly reduce the burden of registration. In the context of a quality improvement project, the PROCARE Steering Group concluded that detailed clinical data from all centres are still required, which can be reconsidered in the future. Maintenance of a specific database remains of crucial value. Data collection and registration cannot be based on benevolence but should be compensated for.

Neither creatinine nor cystatin C-estimated glomerular filtration rate is optimal in oncology patients treated with targeted agents.

Background In the last decade, there has been an increase in the use of anti-angiogenic drugs as treatment for metastatic malignancies. However, use of these targeted therapies could induce both glomerular and tubular damage. Also during targeted therapy, the lysosomal protease cathepsin D is released from the tumour, which is inhibited by the protease inhibitor cystatin C. The aim of this study is to determine if use of cystatin C-estimated glomerular filtration rate (eGFR) is applicable to a patient cohort treated with targeted agents. Methods A cohort of 80 patients with various malignancies were continuously recruited and prospectively analysed. Serum and urinary biochemical analytes for renal toxicities were assessed at different time points during treatment. The association between serum cystatin C and cathepsin D was also determined. Results A decrease in serum cystatin C concentrations (1.03 versus 0.90 mg/L; P < 0.001), together with an increase in cystatin C-eGFR (71 versus 89 mL/min/1.73 m2; P = 0.002) was observed during therapy, compared with baseline. This decrease in cystatin C concentrations was correlated with cathepsin D (r = 0.307; P < 0.001), which was released from the tumour during targeted therapy. Further analysis demonstrated cathepsin D-mediated proteolysis of cystatin C in serum. Conclusions Cystatin C concentrations were decreased during targeted therapy due to cathepsin D-mediated proteolysis. Cystatin C-eGFR is therefore not considered a suitable marker for assessing kidney function in oncology patients, and other techniques to estimate the GFR have to be applied in this patient population.

Cisplatin-modified de Gramont in second-line therapy for pancreatic adenocarcinoma

Objectives In Belgium, combination chemotherapy of cisplatin and 5-fluorouracil + leucovorin (CFL) according to the modified de Gramont schedule is the treatment of choice in second line for metastatic pancreatic cancer. We retrospectively analyzed survival data in 2 Belgian centers in a nonselected population. Methods Between January 2004 and October 2011, 48 patients with histologically proven recurrent or unresectable pancreatic adenocarcinoma who had received CFL as second-line treatment were identified. We retrospectively analyzed the following parameters: progression-free survival (PFS1 and PFS2) for each line (after the start of first and second line), overall survival (OS), and growth modulation index. Results The median PFS1 was 5.4 months (95% confidence interval [CI], 4.1–6.6). The median PFS2 was 3.6 months (95% CI, 2–5.2). The median OS was 12 months (95% CI, 9.3–14.7). Twenty-three percent of patients had a growth modulation index >1.33. Conclusion We show an OS of 12 months with gemcitabine in first-line and CFL in second-line therapy for pancreatic cancer. Sequential therapy with good OS and good quality of life may be preferred to strong upfront therapy in an incurable disease such as pancreatic cancer.

The inflammatory response to stress and angiogenesis in liver resection for colorectal liver metastases: a randomised controlled trial comparing open versus laparoscopic approach

Abstract Background: This study evaluates the surgical stress response following laparoscopic and open liver resection for colorectal liver metastasis (CRLM). Methods: Patients with CRLM were prospectively randomized to receive open or laparoscopic liver resection (NCT03131778). Blood samples were drawn preoperatively and 24 h after resection. The serum interleukin-6 (IL-6) and IL-8 levels were measured. Furthermore, the mRNA levels of angiogenesis-related factors (vascular endothelial growth factor [VEGF] and HIF-1) and inflammation-related factors (COX-2 and MMP-9) in both tumor tissue and normal liver parenchyma were detected. Results: Twenty patients for each arm were included. Size of metastasis, type of resection, and neoadjuvant therapy were comparable between groups. Postoperative stay was shorter in the laparoscopic group. Higher levels of IL-6 were observed after the operation in both open and laparoscopic groups, although no differences in the post-operative levels between the groups was noted. Similarly, there were no significant differences in the mRNA expression of VEGF, HIF-1, MMP-9, and COX-2 between the treatment groups. No differences were observed in terms of overall survival and disease free survival. Conclusions: The immunological effects of treatment were similar between the groups. Thus, the laparoscopic approach does not seem to significantly influence the surgical stress and tumor related factors in patients suffering from colorectal liver metastases.