Levels of Evidence Supporting United States Guidelines in Pancreatic Adenocarcinoma Treatment.

Cancer guidelines are ideally based on high levels of evidence (LOE). We aim to evaluate the LOE supporting recommendations in United States (US) guidelines on pancreatic adenocarcinoma (PDAC) treatment and its evolution over time. We searched for current guidelines from the American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN) and their prior publicly available versions on societies' websites and/or MEDLINE. We recorded the LOE and class of recommendation (opinion of the writing panel) for each recommendation. We defined high LOE as: a "high" quality of evidence from the GRADE methodology (ASCO) and "Category 1" (NCCN). Our main outcome was the proportion of PDAC recommendations supported by high LOE. Proportions of high LOE recommendations were 5% (2/40) and 8% (12/153) in current ASCO and NCCN guidelines, respectively. Less than 10% of class I recommendations were based on high LOE. For NCCN guidelines, the proportion of high LOE recommendations did not improve over time and only three recommendations increased their LOE. We identified a small percentage of high LOE recommendations for PDAC treatment in US guidelines. However, guidelines authors can only deal with the available evidence. The current framework of evidence should be challenged with consideration of observational evidence.

Good clinical practice recommendations for the use of PET/CT in oncology.

Positron emission tomography/computed tomography (PET/CT) is a nuclear medicine functional imaging technique with proven clinical value in oncology. PET/CT indications are continually evolving with fresh advances made through research. French practice on the use of PET in oncology was framed in recommendations based on Standards-Options-Recommendations methodology and coordinated by the French federation of Comprehensive Cancer Centres (FNLCC). The recommendations were originally issued in 2002 followed by an update in 2003, but since then, a huge number of scientific papers have been published and new tracers have been licenced for market release. The aim of this work is to bring the 2003 version recommendations up to date. For this purpose, a focus group was set up in collaboration with the French Society for Nuclear Medicine (SFMN) to work on developing good clinical practice recommendations. These good clinical practice recommendations have been awarded joint French National Heath Authority (HAS) and French Cancer Institute (INCa) label status-the stamp of methodological approval. The present document is the outcome of comprehensive literature review and rigorous appraisal by a panel of experts, organ specialists, clinical oncologists, surgeons and imaging specialists. These data were also used for the EANM referral guidelines.

Early decrease in serum amphiregulin or vascular endothelial growth factor levels predicts sorafenib efficacy in hepatocellular carcinoma.

Sorafenib is the standard of care for the treatment of advanced hepatocellular carcinoma (HCC). However, identifying secreted biomarkers that predict sorafenib efficacy in all HCC patients remains challenging. It was recently reported that sorafenib interferes with protein homeostasis and inhibits global translation in tumour cells. A likely consequence of this inhibition would be the interruption of autocrine loops. The aim of the present study was to investigate the effect of sorafenib on two growth factors implicated in autocrine loops and HCC tumour invasion: amphiregulin (AREG) and vascular endothelial growth factor (VEGF). ELISA, quantitative polymerase chain reaction analysis, western blotting and a cytokine array were performed on HCC cell lines and the prognostic role of these two biomarkers in HCC patients was evaluated. Serum AREG and VEGF levels were assayed by ELISA in 55 patients with advanced HCC treated with sorafenib. It was observed that sorafenib decreased AREG, VEGF and cytokine expression at the transcriptional and post­transcriptional levels. All HCC patients in our cohort had detectable concentrations of AREG and VEGF both at baseline and after sorafenib treatment. The decreased serum levels of AREG and VEGF after 15 days of sorafenib treatment were significantly associated with better overall and progression­free survival. The results of the multivariate analysis demonstrated that a decrease in AREG was an independent prognostic indicator of overall survival (hazard ratio, 0.208; 95% confidence interval, 0.173­0.673; P=0.0003). These results suggest that sorafenib inhibits auto-crine loops and that early decrease in serum AREG or VEGF levels predicts sorafenib efficacy in HCC patients.

[Tyrosine kinase inhibiting the VEGF pathway and elderly people: Tolerance, pre-treatment assessment and side effects management]. / Inhibiteurs de tyrosine kinase ciblant l'angiogenèse et sujets âgés : tolérance, évaluation pré-thérapeutique et gestion des effets indésirables.

Angiogenesis inhibition is a major antitumor strategy that has emerged during the last decade. Oral tyrosine kinase inhibitors (TKI) targeting the VEGF receptor, including sunitinib, sorafenib, axitinib, regorafenib, pazopanib, and vandetanib reduce tumor growth and metastasis. These agents are approved for the treatment of metastatic diseases in first or second-line. They display a narrow therapeutic index. However, data in the elderly and/or in patients with multiple illnesses remain scarce. This population is classically excluded from clinical trials. The aim of this review is to provide an overview of existing literature regarding antiangiogenic TKI tolerance in the elderly (>70 years old). We also highlight key points of the pre-therapeutic evaluation and summarize the management of common toxicities.

Diagnosis of Iron Deficiency in Inflammatory Bowel Disease by Transferrin Receptor-Ferritin Index.

Iron deficiency is common in patients with inflammatory bowel disease (IBD), but can be difficult to diagnose in the presence of inflammation because ferritin is an acute phase reactant. The transferrin receptor-ferritin index (TfR-F) has a high sensitivity and specificity for iron deficiency diagnosis in chronic diseases. The diagnostic efficacy of TfR-F is little known in patients with IBD. The aim of the study was to assess the added value of TfR-F to iron deficiency diagnosis in a prospective cohort of patients with IBD.Consecutive IBD patients were prospectively enrolled. Patients were excluded in case of blood transfusion, iron supplementation, or lack of consent. IBD activity was assessed on markers of inflammation (C-reactive protein, endoscopy, fecal calprotectin). Hemoglobin, ferritin, vitamin B9 and B12, Lactate dehydrogenase, haptoglobin, and soluble transferrin receptor (sTfR) were assayed. TfR-F was calculated as the ratio sTfR/log ferritin. Iron deficiency was defined by ferritin <30 ng/mL or TfR-F >2 in the presence of inflammation.One-hundred fifty patients with median age 38 years (16-78) and Crohn disease (n = 105), ulcerative colitis (n = 43), or unclassified colitis (n = 2) were included. Active disease was identified in 45.3%. Anemia was diagnosed in 28%. Thirty-six patients (24%) had ferritin <30 ng/mL. Thirty-two patients (21.3%) had ferritin levels from 30 to 100 ng/ml and inflammation: 2 had vitamin B12 deficiency excluding TfR-F analysis, 13 of 30 (43.3%) had TfR-F >2. Overall, iron deficiency was diagnosed in 32.7% of the patients.TfR-F in addition to ferritin <30 ng/mL criterion increased by 36% diagnosis rates of iron deficiency. TfR-F appeared as a useful biomarker that could help physicians to diagnose true iron deficiency in patients with active IBD.

[Biotherapies in metastatic colorectal cancers in 2014]. / Les biothérapies des cancers colorectaux métastatiques en 2014.

The treatment of metastatic colorectal cancer has been transformed during the last decade with biotherapies, two of them were marketed in 2013. Four agents are monoclonal antibodies, while the fifth agent is a tyrosine kinase inhibitor. Two agents are inhibitors of the EGF-receptor pathway, cetuximab and panitumumab, and have as class-toxicity, cutaneous toxicity. The other three agents are bevacizumab, aflibercept and regorafenib, and interact with angiogenesis, they are associated with a risk of vascular toxicity, mainly hypertension. These agents participate to an improvement of disease control at the metastatic stage, and in some cases, favour the curative surgical resection of metastases. Their use is discussed in multidisciplinary meetings dedicated to gastrointestinal cancers, in the presence of liver surgeons.

Drug safety evaluation of sorafenib for treatment of solid tumors: consequences for the risk assessment and management of cancer patients.

INTRODUCTION: Sorafenib is a multi-tyrosine kinase inhibitor (TKI). Considerable clinical experience has been accumulated since its first Phase III clinical trial in metastatic renal cancer patients in 2007. The management of its early acute toxicity in fit patients is well known. The management of prolonged treatment becomes the new challenge. AREAS COVERED: Using sorafenib as a key word for PubMed search, we review preclinical and clinical data and discuss the pharmacokinetics and pharmacodynamics of sorafenib, its acute and cumulative toxicities and their consequences for patient management. EXPERT OPINION: The systematic multi-disciplinary risk assessment of cancer patients prior to TKI initiation reduces the risks of acute and late toxicity, especially drug-drug interactions and arterial risks. Sarcopenia is now identified as a major risk of severe toxicity. The very diverse clinical pictures of cumulative toxicity must be known. The monitoring of sorafenib systemic exposure is helpful especially in elderly patients. Moreover, at disease progression, it allows distinguishing between underexposure to sorafenib and truly acquired resistance to the drug. The optimal use of sorafenib should allow improving the reported results of flat-dose. Finally, most of this knowledge could be used for the development and optimal use of the other TKIs.

Treatment of oxaliplatin-induced peripheral neuropathy by intravenous mangafodipir.

BACKGROUND: The majority of patients receiving the platinum-based chemotherapy drug oxaliplatin develop peripheral neurotoxicity. Because this neurotoxicity involves ROS production, we investigated the efficacy of mangafodipir, a molecule that has antioxidant properties and is approved for use as an MRI contrast enhancer. METHODS: The effects of mangafodipir were examined in mice following treatment with oxaliplatin. Neurotoxicity, axon myelination, and advanced oxidized protein products (AOPPs) were monitored. In addition, we enrolled 23 cancer patients with grade ≥ 2 oxaliplatin-induced neuropathy in a phase II study, with 22 patients receiving i.v. mangafodipir following oxaliplatin. Neuropathic effects were monitored for up to 8 cycles of oxaliplatin and mangafodipir. RESULTS: Mangafodipir prevented motor and sensory dysfunction and demyelinating lesion formation. In mice, serum AOPPs decreased after 4 weeks of mangafodipir treatment. In 77% of patients treated with oxaliplatin and mangafodipir, neuropathy improved or stabilized after 4 cycles. After 8 cycles, neurotoxicity was downgraded to grade ≥ 2 in 6 of 7 patients. Prior to enrollment, patients received an average of 880 ± 239 mg/m2 oxaliplatin. Patients treated with mangafodipir tolerated an additional dose of 458 ± 207 mg/m2 oxaliplatin despite preexisting neuropathy. Mangafodipir responders managed a cumulative dose of 1,426 ± 204 mg/m2 oxaliplatin. Serum AOPPs were lower in responders compared with those in nonresponders. CONCLUSION: Our study suggests that mangafodipir can prevent and/or relieve oxaliplatin-induced neuropathy in cancer patients. Trial registration. Clinicaltrials.gov NCT00727922. Funding. Université Paris Descartes, Ministère de la Recherche et de l'Enseignement Supérieur, and Assistance Publique-Hôpitaux de Paris.

Iron deficiency: from diagnosis to treatment.

Iron deficiency is the most frequent cause of anaemia worldwide. It impairs quality of life, increases asthenia and can lead to clinical worsening of patients. In addition, iron deficiency has a complex mechanism whose pathologic pathway is recently becoming better understood. The discovery of hepcidin has allowed a better clarification of iron metabolism regulation. Furthermore, the ratio of concentration of soluble transferrin receptor to the log of the ferritin level, has been developed as a tool to detect iron deficiency in most situations. The cause of iron deficiency should always be sought because the underlying condition can be serious. This review will summarize the current knowledge regarding diagnostic algorithms for iron deficiency anaemia. The majority of aetiologies occur in the digestive tract, in men and postmenopausal women, and justify morphological examination of the gut. First line investigations are upper gastrointestinal endoscopy and colonoscopy, and when negative, the small bowel should be explored; newer tools such as video capsule endoscopy have also been developed. The treatment of iron deficiency is aetiological if possible and iron supplementation whether in oral or in parenteral form. New parenteral formulations are available and seem to have promising results in terms of efficacy and safety.

Cost effectiveness of integrated medicine in patients with cancer receiving anticancer chemotherapy.

PURPOSE: Ambulatory chemotherapy is patient friendly but may result in toxicity-induced unscheduled hospitalizations (TIUHs). This emerging issue may increase health care costs. We studied the cost effectiveness of a hospital-home monitoring program based on systematic iterative telephone calls after chemotherapy. PATIENTS AND METHODS: We retrospectively evaluated the rates of chemotherapy-induced unscheduled hospitalizations in patients who were treated in August 2008. Patients were contacted by telephone 1 day before chemotherapy and on the second and eighth days after undergoing chemotherapy. Costs associated with TIUHs were calculated and compared with those of a cohort concomitantly treated using the standard follow-up procedure. RESULTS: A total of 259 patients entered the hospital-home monitoring program. They were compared with 86 patients who had similar characteristics but underwent the standard treatment and follow-up procedure. Inclusion in the hospital-home monitoring program resulted in patients experiencing TIUHs approximately half as frequently as patients in the other group (2.4% v 4.9%; P < .01). Patients in the program experienced TIUHs for a median length of stay of 4 days, representing a nonsignificant reduction in duration of hospitalization (P not significant). Consequently, through a two-fold reduction in TIUH annual incidence, this program represents a reduction in unscheduled hospitalizations per year of 383 days, decreasing hospital costs by €201.468 ($292,468) per year. CONCLUSION: The hospital-home monitoring program is a cost-effective strategy for offering ambulatory chemotherapy treatment to patients with cancer. This program has become our standard procedure for ambulatory chemotherapy in patients with cancer.

Sorafenib-induced hepatocellular carcinoma cell death depends on reactive oxygen species production in vitro and in vivo.

Sorafenib is presently the only effective therapy in advanced hepatocellular carcinoma (HCC). Because most anticancer drugs act, at least in part, through the generation of reactive oxygen species, we investigated whether sorafenib can induce an oxidative stress. The effects of sorafenib on intracellular ROS production and cell death were assessed in vitro in human (HepG2) and murine (Hepa 1.6) HCC cell lines and human endothelial cells (HUVEC) as controls. In addition, 26 sera from HCC patients treated by sorafenib were analyzed for serum levels of advanced oxidation protein products (AOPP). Sorafenib significantly and dose-dependently enhanced in vitro ROS production by HCC cells. The SOD mimic MnTBAP decreased sorafenib-induced lysis of HepG2 cells by 20% and of Hepa 1.6 cells by 75% compared with HCC cells treated with 5 mg/L sorafenib alone. MnTBAP significantly enhanced by 25% tumor growth in mice treated by sorafenib. On the other hand, serum levels of AOPP were higher in HCC patients treated by sorafenib than in sera collected before treatment (P < 0.001). An increase in serum AOPP concentration ≥0.2 µmol/L chloramine T equivalent after 15 days of treatment is a predictive factor for sorafenib response with higher progression free survival (P < 0.05) and overall survival rates (P < 0.05). As a conclusion, sorafenib dose-dependently induces the generation of ROS in tumor cells in vitro and in vivo. The sera of Sorafenib-treated HCC patients contain increased AOPP levels that are correlated with the clinical effectiveness of sorafenib and can be used as a marker of effectiveness of the drug. .

Gemcitabine and oxaliplatin as second-line treatment in patients with hepatocellular carcinoma pre-treated with sorafenib.

Some patients with advanced hepatocellular carcinoma (HCC) progressing under sorafenib remain eligible for further systemic therapy. Little is known on the feasibility of systemic treatment beyond sorafenib in this setting. Consecutive HCC patients pre-treated with sorafenib received gemcitabine 1,000 mg/m² and oxaliplatin 100 mg/m² every 14 days. Exclusion criteria included Child C cirrhosis, PS≥3, creatinine clearance<20 ml/min, albumin<25 g/L and bilirubin>54 µmol/L. Pre-treatment body composition was evaluated by CT scan to detect muscle wasting (sarcopenia). The primary evaluation criterion was safety. Secondary evaluation criteria were response rate, and progression-free (PFS) and overall survival (OS). Eighteen patients (median age: 64 years, range 25-77) received a total of 90 cycles (median per patient: 4, range 1-16). Eight patients (44.4 %) had a PS of 2, 5 (27.8%) had Child-Pugh B cirrhosis and 13 (72.2%) had a CLIP score>3. The most frequent toxicities were thrombocytopenia (grade 2-4: n=7, 38.9%) and peripheral neuropathy (grade 2-3: n=7, 38.9%). The overall response rate was 18.8% (95% CI: 0-37.9), and another 18.8 % of patients had stable disease. The median PFS and OS were 3.2 (95% CI: 2.3-3.9) and 4.7 (95% CI: 3.8-8.1) months, respectively. Overall survival was significantly longer in patients without sarcopenia [10.0 months (95% CI: 7.0-13.8) vs. 3.0 months (95 % CI: 2.5-3.9), p<0.001] and in patients with an ECOG PS<2 [8.1 months (95% CI: 7.0-13.8) vs. 3.8 months (95% CI: 2.5-3.9), p=0.017]. In our experience, gemcitabine-oxaliplatin was feasible and had detectable clinical activity in HCC patients pre-treated with sorafenib. Further studies are needed to confirm these findings.

Feasibility of oxaliplatin, 5-fluorouracil and leucovorin (FOLFOX-4) in cirrhotic or liver transplant patients: experience in a cohort of advanced hepatocellular carcinoma patients.

PURPOSE: The only drug that improves survival in hepatocellular carcinoma is sorafenib. FOLFOX-4 regimen is safe and widely used in patients with colorectal cancer, yielding interesting results with little toxicity. We conducted a retrospective study to evaluate the safety and the effectiveness of FOLFOX-4 in cirrhotic or liver transplanted patients with hepatocellular carcinoma ineligible for sorafenib. METHODS: Thirty seven patients were enrolled in the study. The medical record of either cirrhotic patients or liver transplanted patients with advanced hepatocellular carcinoma receiving FOLFOX-4 regimen between November 1999 and March 2006 were retrospectively analyzed. Patients received oxaliplatin 85 mg/m(2) as a 2-hour infusion on day one, and leucovorin 200 mg/m(2) as a 2-hour infusion followed by bolus 5-fluorouracil 400 mg/m(2) and a 48-hours infusion of 5-fluorouracil 2400 mg/m(2). Treatment was repeated every 2 weeks until disease progression or unacceptable adverse effects occurred. RESULTS: Patients had a Child-Pugh class A (n = 16), class B cirrhosis (n = 10) or a liver transplant (n = 11) and received 2 to 37 cycles of chemotherapy (total of 310 cycles). Two (5.4%) cirrhotic patients developed neutropenic sepsis and one (2.7%) toxic death occurred. At first assessment, five patients from Child-Pugh class A (33%) and two from Child-Pugh class B group (20%) achieved a radiological response and/or alpha foeto-protein decrease, and no patient achieved a complete response. CONCLUSIONS: In conclusion, with a manageable toxicity profile in cirrhotic Child-Pugh class A-B or liver transplanted patients, the FOLFOX-4 regimen appears to be a feasible treatment option for patients with advanced hepatocellular carcinoma unfit for sorafenib. These data need to be confirmed in a prospective study.

[Is there alternative to FOLFOX adjuvant chemotherapy for stage III colorectal cancer patients?]. / Existe-t-il une alternative à la chimiothérapie adjuvante par FOLFOX dans les cancers coliques de stade III ?

Being the second cancer for men and the third cancer for women in France, colorectal cancer represents a serious public health issue. Its incidence has increased these last years and despite new therapeutics being developed, it still has a bad prognostic. Thanks in part to Hemoccult national mass screening program, its diagnosis is made possible at an earlier stage, which makes a surgical curative resection and the carrying out of adjuvant chemotherapy possible. For stage III colic cancer that has been surgically removed, adjuvant chemotherapy by FOLFOX 4 has to be offered. Nevertheless, because of its toxicities, the patient's high age, important comorbidities or post-surgical complications, this chemotherapy occasionally cannot be done. What are the colorectal cancer prognostic factors which would guide the chemotherapy? TNM classification, number of examined lymph nodes, MSI status, and presence or not of a perforation or a perinervous, lymphatic or venous invasion is recognized prognostic factors. Also, what are the alternatives of FOLFOX 4 regimen as colorectal cancer adjuvant treatment?

Reversible decrease of portal venous flow in cirrhotic patients: a positive side effect of sorafenib.

Portal hypertension, the most important complication with cirrhosis of the liver, is a serious disease. Sorafenib, a tyrosine kinase inhibitor is validated in advanced hepatocellular carcinoma. Because angiogenesis is a pathological hallmark of portal hypertension, the goal of our study was to determine the effect of sorafenib on portal venous flow and portosystemic collateral circulation in patients receiving sorafenib therapy for advanced hepatocellular carcinoma. Porto-collateral circulations were evaluated using a magnetic resonance technique prior sorafenib therapy, and at day 30. All patients under sorafenib therapy had a decrease in portal venous flow of at least 36%. In contrast, no specific change was observed in the azygos vein or the abdominal aorta. No portal venous flow modification was observed in the control group. Sorafenib is the first anti-angiogenic therapy to demonstrate a beneficial and reversible decrease of portal venous flow among cirrhotic patients.

Pneumatosis intestinalis associated with treatment of cancer patients with the vascular growth factor receptor tyrosine kinase inhibitors sorafenib and sunitinib.

Recently, pneumatosis intestinalis has been described in patients receiving bevacizumab, a monoclonal antibody to VEGF-A. Pneumatosis intestinalis is a condition characterized by subserosal and submucosal gas-filled cysts in the gastrointestinal tract. We report on pneumatosis intestinalis in patients receiving oral anti-VEGF agents. Patients shared the following characteristics: long-term (> 4 months) exposure to anti-VEGF agents, lack of other factors predisposing to pneumatosis intestinalis, and lack of recent surgical intervention. Taken together, these observations suggest that pneumatosis intestinalis is a probable class-effect of anti-VEGF agents.