Sorafenib increases 18-FDG colic uptake: demonstration in patients with differentiated thyroid cancer

BACKGROUND: To assess 18-fluorodeoxyglucose (FDG) bowel uptake in patients with differentiated thyroid cancer (DTC) treated with sorafenib. FINDINGS: Visual (5-point scale) and high maximum standard uptake value (SUVmax) semi-quantitative analyses were conducted in 63 positron emission tomography (PET) studies performed in patients on sorafenib (group 1, n = 20), in a control group (group 2, n = 28) and in patients on sunitinib or vandetanib (group 3, n = 15). Moderate or high and diffuse bowel uptake (grade 4 or 5) was observed in 90% of the PET scans of group 1 versus none in group 2. Only 20% of PET scans in group 3 were scored grade 4. SUVmax values were significantly higher for all colic segments in group 1 than in group 2 (P < 0.0001) or 3 (P < 0.0004). This uptake pattern appeared rapidly (one month) and disappeared after sorafenib withdrawal. CONCLUSIONS: FDG uptake is increased in the colon of DTC patients treated by sorafenib

Anti-cetuximab IgE ELISA for identification of patients at a high risk of cetuximab-induced anaphylaxis

Cetuximab, a chimeric mouse-human IgG1 monoclonal antibody against the epidermal growth factor receptor, has proven effective in the treatment of metastatic colorectal cancer and squamous cell carcinoma of the head and neck. However, a high incidence of immediate hypersensitivity reactions (HSR) to cetuximab after the first infusion has been observed. We have developed a test for identification of patients likely to show treatment-related HSR to cetuximab. An enzyme-linked immunosorbent assay (ELISA) for detecting anti-cetuximab IgEs was developed and tested on serum samples collected from cancer patients before start of cetuximab treatment, and from healthy blood donors. Similar levels of anti-cetuximab IgE were detected in pre-treatment patient sera (24/92, 26.1%) and sera from healthy blood donors (33/117, 28.2%). HSR were observed in 14 out of the 92 patients (15.2%), and 8 of these (57.1%) were grade 3–4. Anti-cetuximab IgEs were detected in 7/8 of the patients (87.5%) with severe HSRs as compared with 14/78 patients (17.9%) with no HSR (p = 0.0002). Predictive value of the anti-cetuximab IgE test for HSR events of grades 3–4 was calculated using Receiver Operating Characteristics analysis. With a cut-off value of 29 arbitrary units for the anti-cetuximab IgE, the ELISA test showed a sensitivity of 87.5%, specificity of 82.1%, positive predictive value of 33.3% and negative predictive value of 98.5%. Anti-cetuximab IgE ELISA detection could be a valuable tool to help the physician anticipate an anaphylaxis episode following cetuximab infusion and opt for a suitable alternative treatment

SOCRATE-PRODIGE 55 trial: A randomized phase II study to evaluate second-line ramucirumab alone or with paclitaxel in older patients with advanced gastric cancer

International audienceINTRODUCTION: Patients ≥ 70 years old constitute 40% of patients with advanced gastric cancer (GC). Ramucirumab plus Paclitaxel is a therapeutic option validated in the second-line treatment of advanced GC, but as older patients are at higher risk of severe toxicity, due to comorbidities and/or frailty, we aimed to evaluate second-line Ramucirumab alone or combined with Paclitaxel in terms of overall survival (OS) and quality of life (QoL) in patients ≥ 70 years-old with advanced GC. METHODS: In this multicenter, randomized, open-label, non-comparative, prospective phase II clinical trial, the main inclusion criteria are: patients ≥ 70 years old, with advanced GC having progressed after first-line chemotherapy or in the six months following the last administration of adjuvant chemotherapy, with WHO performance status &lt;2. They are randomized to receive either ramucirumab alone (arm A) or ramucirumab plus Paclitaxel (arm B). The primary endpoint is 6-month OS and QoL evaluated with the EORTC QLQ-ELD14 questionnaire. The secondary endpoints include other parameters of QoL, time to definitive deterioration (TTDD) in QoL and TTDD in autonomy, treatment toxicities, other parameters of survival and disease control, identification of geriatric and nutritional prognostic scores and predictive factors of treatment safety and efficacy. OS of 60% is expected at 6 months (H0:40%). Using a Simon-minimax design, with one-sided α risk of 2% and 80% power for OS, and considering 5% lost to follow-up, it is necessary to randomize 56 patients in each arm. PERSPECTIVES: As older patients are at higher risk of chemotherapy toxicity, ramucirumab alone could be an interesting alternative to Paclitaxel plus ramucirumab, as a second-line therapy for patients ≥ 70 years old with advanced GC, and needs to be evaluated

Definitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ACCORD17): final results of a randomised, phase 2/3 trial

International audienceBackgroundDefinitive chemoradiotherapy is a curative treatment option for oesophageal carcinoma, especially in patients unsuitable for surgery. The PRODIGE5/ACCORD17 trial aimed to assess the efficacy and safety of the FOLFOX treatment regimen (fluorouracil plus leucovorin and oxaliplatin) versus fluorouracil and cisplatin as part of chemoradiotherapy in patients with localised oesophageal cancer.MethodsWe did a multicentre, randomised, open-label, parallel-group, phase 2/3 trial of patients aged 18 years or older enrolled from 24 centres in France between Oct 15, 2004, and Aug 25, 2011. Eligible participants had confirmed stage I–IVA oesophageal carcinoma (adenocarcinoma, squamous-cell, or adenosquamous), Eastern Cooperative Oncology Group (ECOG) status 0–2, sufficient caloric intake, adequate haematological, renal, and hepatic function, and had been selected to receive definitive chemoradiotherapy. Patients were randomly assigned (1:1) to receive either six cycles (three concomitant to radiotherapy) of oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, bolus fluorouracil 400 mg/m2, and infusional fluorouracil 1600 mg/m2 (FOLFOX) over 46 h, or four cycles (two concomitant to radiotherapy) of fluorouracil 1000 mg/m2 per day for 4 days and cisplatin 75 mg/m2 on day 1. Both groups also received 50 Gy radiotherapy in 25 fractions (five fractions per week). Random allocation to treatment groups was done by a central computerised randomisation procedure by minimisation, stratified by centre, histology, weight loss, and ECOG status, and was achieved independently from the study investigators. The primary endpoint was progression-free survival. Data analysis was primarily done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00861094.Findings134 participants were randomly allocated to the FOLFOX group and 133 to the fluorouracil and cisplatin group (intention-to-treat population), and 131 patients in the FOLFOX group and 128 in the fluorouracil and cisplatin group actually received the study drugs (safety population). Median follow-up was 25·3 months (IQR 15·9–36·4). Median progression-free survival was 9·7 months (95% CI 8·1–14·5) in the FOLFOX group and 9·4 months (8·1–10·6) in the fluorouracil and cisplatin group (HR 0·93, 95% CI 0·70–1·24; p=0·64). One toxic death occurred in the FOLFOX group and six in the fluorouracil–cisplatin group (p=0·066). No significant differences were recorded in the rates of most frequent grade 3 or 4 adverse events between the treatment groups. Of all-grade adverse events that occurred in 5% or more of patients, paraesthesia (61 [47%] events in 131 patients in the FOLFOX group vs three [2%] in 128 patients in the cisplatin–fluorouracil group, p<0·0001), sensory neuropathy (24 [18%] vs one [1%], p<0·0001), increases in aspartate aminotransferase concentrations (14 [11%] vs two [2%], p=0·002), and increases in alanine aminotransferase concentrations (11 [8%] vs two [2%], p=0·012) were more common in the FOLFOX group, whereas serum creatinine increases (four [3%] vs 15 [12%], p=0·007), mucositis (35 [27%] vs 41 [32%], p=0·011), and alopecia (two [2%] vs 12 [9%], p=0·005) were more common in the fluorouracil and cisplatin group.InterpretationAlthough chemoradiotherapy with FOLFOX did not increase progression-free survival compared with chemoradiotherapy with fluorouracil and cisplatin, FOLFOX might be a more convenient option for patients with localised oesophageal cancer unsuitable for surgery

Hepatic arterial oxaliplatin plus intravenous 5-fluorouracil and cetuximab for first-line treatment of colorectal liver metastases: A multicenter phase II trial

International audienceBackground: The efficacy and tolerability of hepatic arterial infusion (HAI) oxaliplatin plus systemic 5-fluorouracil and cetuximab as frontline treatment in patients with colorectal liver metastases (CRLM) are unknown. Methods: In this multicenter, single-arm phase II study, patients with CRLM not amenable to curative-intent resection or requiring complex/major liver resection, and no prior chemotherapy for metastatic disease, received HAI oxaliplatin and intravenous 5-fluorouracil, leucovorin and cetuximab, every two weeks until disease progression, limiting toxicity or at least 3 months after complete response or curative-intent resection/ablation. The primary endpoint was overall response rate (ORR). Results: 35 patients, mostly with bilateral (89%), multiple CRLM (>4, 86%; >10, 46%) were enrolled in eight centers. The ORR was 88% (95% CI, 71%−96%) among evaluable patients (n = 32), and 95% (95% CI 70–100%) among the 22 wild-type RAS/BRAF evaluable patients. After a median follow-up of 8.8 years (95% CI, 8.7-not reached), median progression-free survival was 17.9 months (95% CI, 15–23) and median overall survival (OS) was 46.3 months (95% CI, 40.0-not reached). 23 of the 35 patients (66%), including 22 (79%) of the 25 patients with wild-type RAS tumor, underwent curative-intent surgical resection and/or ablation of CRLM. HAI catheter remained patent in 86% of patients, allowing for a median of eight oxaliplatin infusions (range, 1–19). Treatment toxicity was manageable, without toxic death. Conclusion: HAI oxaliplatin plus systemic 5-fluorouracil and cetuximab appears highly effective in the frontline treatment of patients with unresectable CRLM and should be investigated further