Pierre Michel

The predictive value of treatment response using FDG PET performed on day 21 of chemoradiotherapy in patients with oesophageal squamous cell carcinoma. A prospective, multicentre study (RTEP3)

PurposeFDG PET has been suggested to have predictive value in the prognosis of oesophageal carcinoma. However, the retrospective studies reported in the literature have shown discordant results. Additionally, only four studies have evaluated FDG PET during chemoradiotherapy (CRT) in patients with different histological lesions. The purpose of this study was to investigate the predictive value of FDG PET performed early during CRT (on day 21) in a population of patients with oesophageal squamous cell carcinoma.MethodsIncluded in this prospective study were 57 patients with a histological diagnosis of squamous cell carcinoma of the oesophagus. Of these 57 patients, 48 (84xa0%) were evaluated (aged 63u2009±u200911xa0years; 44 men, 4 women). Each patient underwent FDG PET (4.5xa0MBq/kg) before CRT, according to the Herskovic protocol (t0; PET1) and on day 21u2009±u20093 from the start of CRT (d21; PET2). The response assessment included a clinical examination, CT scan or FDG PET and histological analysis 3xa0months and 1xa0year after PET1. The patients were classified as showing a complete response (CR) or a noncomplete response. A quantitative analysis was carried out for PET1 and PET2 using the following parameters: SUVmax, SUVmean (with SUVmean40 as the 3-D volume at an SUVmax threshold of 40xa0% and SUVmeanp as that defined by a physician), tumour volume (TV, with TV40 defined as the TV at 40xa0% of SUVmax, and TVp as that defined by a physician); and the total lesion glycolysis (TLG, SUVmean × TV, with TLG40 defined as the TLG at 40xa0% of SUVmax, and TLGp as that defined by a physician). The differences in responses at 3xa0months and 1xa0year between PET1 (t0) and PET2 (d21) were assessed in terms of variations in SUV, TV and TLG using a repeated measures of variance (ANOVA).ResultsSUVmax, SUVmean and TLG decreased significantly between PET1 (t0) and PET2 (d21; pu2009<u20090.0001). The TV significantly decreased only when assessed as TVp (pu2009=u20090.02); TV40 did not decrease significantly. With respect to the predictive value of PET1, only TV40_1 and TVp_1 values, and therefore TLG40_1 and TLGp_1, but not the SUV values, were significantly lower in patients with CR at 3xa0months. SUVmax1, TVp_1 and TLGp_1 were significantly lower in patients with CR at 1xa0year. With respect to the predictive value of PET2, only TV40_2 and TVp_2 values, and therefore TLG40_2 and TLGp_2, but not the SUV values, were significantly lower in patients with CR at 3xa0months. None of the PET2 parameters had significant value in predicting patient outcome at 1xa0year. The changes in SUVmax, TV40, TVp, TLG40 and TLGp between PET1 and PET2 had no relationship to patient outcome at 3xa0months or 1xa0year.ConclusionThis prospective, multicentre study performed in a selected population of patients with oesophageal squamous cell cancer demonstrates that the parameters derived from baseline PET1 are good predictors of response to CRT. Specifically, a high TV and TLG are associated with a poor response to CRT at 3xa0months and 1xa0year, and a high SUVmax is associated with a poor response to CRT at 1xa0year. FDG PET performed during CRT on day 21 appears to have less clinical relevance. However, patients with a large functional TV on day 21 of CRT have a poor clinical outcome (ClinicalTrials.gov NCT 00934505).

Lugol chromo-endoscopy versus Narrow Band Imaging for endoscopic screening of esophageal squamous-cell carcinoma in patients with a history of cured esophageal cancer: a feasibility study

To date, Lugol chromo-endoscopy is the reference technique to detect an esophageal neoplasia in patients with prior esophageal squamous-cell carcinoma (ESCC), but is not easy to perform without general anesthesia, which can limit its use in routine practice. The objective of this study were to compare the accuracy of white light, narrow band imaging (NBI), and Lugol to detect esophageal neoplasia in patients with a history of cured ESCC, in a prospective study. Thirty patients were prospectively included between June 2006 and June 2009. They all had a history of cured ESCC. Esophageal mucosa was examined first using white light, second NBI, and third after Lugol staining. Histology was obtained in all abnormalities detected by white light, NBI, and/or Lugol. Five neoplastic lesions in five different patients were identified at histology, four cancers, and one high-grade dysplasia. NBI and Lugol both detected all esophageal neoplastic lesions, whereas white light detected the four cancers but missed the high-grade dysplasia. In this feasibility study, NBI and Lugol both detected all identified esophageal neoplasia in very high-risk patients of ESCC. This result suggests that NBI could be used instead of Lugol to detect an esophageal neoplasia in patients with high risk of ESCC, but needs to be confirmed in a larger study.

Clinical value of chip-based digital-PCR platform for the detection of circulating DNA in metastatic colorectal cancer.

BACKGROUNDnThe detection of circulating DNA is considered a promising strategy in cancer patients. Digital PCR has emerged as a sensitive method able to quantify both circulating free and tumour DNA.nnnAIMnThe aim of this study was to prospectively evaluate the clinical value of a chip-based digital PCR for the detection of circulating DNA.nnnMETHODSnDigital PCR was used in 34 metastatic colorectal cancer patients to detect and quantify circulating free and tumour DNA based on K-ras mutational status. Clinical outcomes were analyzed according to circulating DNA measurements.nnnRESULTSnDigital PCR yielded a detection rate of 69% for circulating tumour DNA. The median concentrations of circulating free and tumour DNA were 20 and 6.8 ng/mL, respectively, with significant correlation between both biomarkers (p<0.001). Median overall survival was 4.8 months in patients with high circulating free DNA (>75% quartile) versus not reached in patients with a low level (<25% quartile) (p=0.029). Moreover, median overall survival was significantly decreased in patients with detectable circulating tumour DNA compared to those without (respectively 11.8 months versus not reached, p=0.04).nnnCONCLUSIONSnChip-based digital PCR is a simple and non-invasive method allowing the efficient detection of circulating DNA. Our results highlight that levels of these circulating markers may have a potential prognostic value.

Role of fluorine 18 fluorodeoxyglucose positron emission tomography/computed tomography in gastrointestinal cancers

Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) has become a routine imaging modality for many malignancies and its use is currently increasing. In the present review article, we will summarize the evidence for FDG-PET/CT use in digestive cancers (excluding neuroendocrine tumours), and review the existing recommendations. While PET/CT is nowadays considered to be an important tool in the initial workup of oesophageal and anal cancers, new data are emerging regarding its use in assessing therapeutic efficacy, radiotherapy treatment planning, and detection of recurrence in case of isolated tumour marker elevation. Moreover, PET/CT may help decision making by detecting distant metastatic sites especially in potentially resectable metastatic colorectal cancer and, to a lesser extent, in localized gastric and pancreatic cancers. Finally, incidental focal colonic FDG uptakes require exploration by colonoscopy, as they are often associated with premalignant or malignant lesions.

FDG-PET/CT during concomitant chemo radiotherapy for esophageal cancer: Reducing target volumes to deliver higher radiotherapy doses

Abstract Background. A planning study investigated whether reduced target volumes defined on FDG-PET/CT during radiotherapy allow total dose escalation without compromising normal tissue tolerance in patients with esophageal cancer. Material and methods. Ten patients with esophageal squamous cell carcinoma (SCC), candidate to curative-intent concomitant chemo-radiotherapy (CRT), had FDG-PET/CT performed in treatment position, before and during (Day 21) radiotherapy (RT). Four planning scenarios were investigated: 1) 50 Gy total dose with target volumes defined on pre-RT FDG-PET/CT; 2) 50 Gy with boost target volume defined on FDG-PET/CT during RT; 3) 66 Gy with target volumes from pre-RT FDG-PET/CT; and 4) 66 Gy with boost target volume from during-RT FDG-PET/CT. Results. The median metabolic target volume decreased from 12.9 cm3 (minimum 3.7–maximum 44.8) to 5.0 cm3 (1.7–13.5) (p = 0.01) between pre- and during-RCT FDG-PET/CT. The median PTV66 was smaller on during-RT than on baseline FDG-PET/CT [108 cm3 (62.5–194) vs. 156 cm3 (68.8–251), p = 0.02]. When total dose was set to 50 Gy, planning on during-RT FDG-PET/CT was associated with a marginal reduction in normal tissues irradiation. When total dose was increased to 66 Gy, planning on during-RT PET yielded significantly lower doses to the spinal cord [Dmax = 44.1Gy (40.8–44.9) vs. 44.7Gy (41.5–45.0), p = 0.007] and reduced lung exposure [V20Gy = 23.2% (17.3–27) vs. 26.8% (19.7–30.2), p = 0.006]. Conclusion. This planning study suggests that adaptive RT based on target volume reduction assessed on FDG-PET/CT during treatment could facilitate dose escalation up to 66 Gy in patients with esophageal SCC.

Monitoring tumour response during chemo-radiotherapy: a parametric method using FDG-PET/CT images in patients with oesophageal cancer

BackgroundThe objective of this study is to investigate the feasibility and the additional interest of a parametric imaging (PI) method to monitor the early tumour metabolic response in a prospective series of oesophageal cancer patients who underwent positron emission tomography with fluoro-2-deoxy-d-glucose (FDG-PET/CT) before and during curative-intent chemo-radiotherapy.MethodsFifty-seven patients with squamous cell carcinoma (SCC) of the oesophagus prospectively underwent FDG-PET/CT before chemo-radiotherapy (CRT) (PET1) and at 21u2009±u20093xa0days after the beginning of CRT (PET2). The outcome was assessed at 3xa0months and 1xa0year after the completion of CRT (clinical examination, CT scan or FDG-PET/CT, biopsy). For each patient, PET1 and PET2 were registered using CT images. The 2 PET image sets were subtracted, so the voxels with significant changes in FDG uptake were identified. A model-based analysis of this graph was used to identify the tumour voxels in which significant changes occurred between the two scans and yielded indices characterising these changes (green and red clusters). Quantitative parameters were compared with clinical outcome at 3xa0months and at 1xa0year.ResultsThe baseline tumour FDG uptake decreased significantly at PET2 (pu2009<u20090.0001). The tumour volume significantly decreased between PET1 and PET2 (pu2009<u20090.02). The initial functional volume of the lesion (TV1) was significantly lower (pu2009<u20090.02) in patients in clinical response (CR) at 3xa0months and 1xa0year. The volume of the lesion during the treatment (TV2) was significantly lower in patients identified as in CR at 3xa0months (pu2009<u20090.03), but did not predict the outcome at 1xa0year. Multivariate analyses of outcome at 3xa0months showed that the risk of failure/death increased with younger age (pu2009=u20090.001), larger metabolic volume on PET1 (pu2009=u20090.009) and larger volume with decreased FDG uptake (pu2009=u20090.047). As for outcome at 1xa0year, the risk of failure/death increased with younger age (pu2009=u20090.006), nodal involvement (pu2009=u20090.08) and larger volumes with increased uptake (pu2009=u20090.03).ConclusionA parametric method to assess tumour response on serial FDG-PET performed during chemo-radiotherapy was evaluated. Early metabolic changes, i.e. variations in FDG uptake, provided additional prognostic information in multivariate analyses ClinicalTrials.gov NCT 00934505.Trial registrationCurrent Controlled Trials ISRCTN7824458

18F-fluorodeoxyglucose positron emission tomography after definitive chemoradiotherapy in patients with oesophageal carcinoma

BACKGROUNDnThe purpose of the study was to investigate the value of 18F-fluorodeoxyglucose-positron emission tomography performed after definitive chemoradiotherapy in patients with locally advanced oesophageal carcinoma.nnnMETHODSnForty consecutive patients underwent 18F-fluorodeoxyglucose-positron emission tomography at baseline and after chemoradiotherapy completion. Assessment of the clinical complete response to chemoradiotherapy included oesophagoscopy plus biopsies and computed tomography scan. Cox regression analysis was used to develop the univariate and multivariate models describing the association of the independent variables with survival and local control.nnnRESULTSnA clinical complete response and 18F-fluorodeoxyglucose-positron emission tomography response were present in 29 patients (72.5%) and 13 patients (32.5%), respectively. A combined response was observed in 11 patients (27.5%). During follow-up, a local failure was detected in 27.2% of patients with 18F-fluorodeoxyglucose-positron emission tomography response versus 33.3% in non-responders (p=.9). In multivariate analysis, clinical complete response (HR 5.77, p=.009) and 18F-fluorodeoxyglucose-positron emission tomography response (HR 6.27, p=.031) were identified as independent prognostic factors of overall survival.nnnCONCLUSIONnIn patients treated for an esophageal cancer, the present study suggested that 18F-fluorodeoxyglucose-positron emission tomography after chemoradiotherapy completion was an independent prognostic factor of overall survival without significant impact on local recurrence prediction.

Association of Prognostic Value of Primary Tumor Location in Stage III Colon Cancer With RAS and BRAF Mutational Status.

Importance We know of no data on the prognostic value of primary tumor location (PTL) according to BRAF, RAS, and microsatellite instability (MSI) status in patients who have undergone resection for colon cancer (CC) and have been treated with current standard adjuvant chemotherapy. Objective To determine the prognostic and predictive value of PTL according to BRAF, RAS, and MSI status in patients with stage III CC receiving adjuvant treatment with FOLFOX (folinic acid [leucovorin calcium], fluorouracil, and oxaliplatin) with or without cetuximab. Design, Setting, and Participants This post hoc analysis included patients with available tumor blocks of resected stage III colon adenocarcinoma who participated in the Pan-European Trials in Alimentary Tract Cancer (PETACC)-8 phase 3 randomized trial. Among the 2559 patients who underwent randomization, 1900 were screened by next-generation sequencing, which showed that 1869 had full information concerning PTL. We categorized primary tumor site as located proximal (right) or distal (left) to the splenic flexure. Main Outcomes and Measures The associations between PTL (right- vs left-sided) and disease-free survival (DFS), survival after relapse (SAR), and overall survival (OS) were assessed by Cox models and adjusted for clinical and pathological features, treatment, and MSI, BRAF, and RAS status. Results Among the 1869 patients (1056 [57%] male; mean [SD] age, 59.4 [9.5] years) with full molecular data analyzed, 755 (40%) had a right-sided tumor, 164 (10%) had MSI, 942 (50%) had RAS mutations, and 212 (11%) had BRAF mutations. Right-sided tumor location was not prognostic for DFS in the whole population but was associated with a shorter SAR (hazard ratio [HR], 1.54; 95% CI, 1.23-1.93; Pu2009=u2009.001) and OS (HR, 1.25; 95% CI, 1.02-1.54; Pu2009=u2009.03). When looking at DFS in the different molecular subgroups, we found similar results for microsatellite-stable tumors and tumors with MSI; a better DFS in right-sided vs left-sided tumors in patients with RAS mutations (HR, 0.80; 95% CI, 0.64-1.00; Pu2009=u2009.046); and a worse DFS in right-sided vs left-sided tumors in patients with RAS and BRAF double wild type (HR, 1.39; 95% CI, 1.01-1.92; Pu2009=u2009.04). These results were found independently of the treatment received, and no beneficial effect of cetuximab on DFS or OS was observed in left-sided tumors. Conclusions and Relevance Although right-sided tumor location is associated with poor survival in patients with metastatic CC as previously reported, the association with disease recurrence appears to vary for patients with stage III CC and RAS or BRAF mutations vs those with double wild type.

High-Dose FOLFIRI plus Bevacizumab in the Treatment of Metastatic Colorectal Cancer Patients with Two Different UGT1A1 Genotypes: FFCD 0504 Study.

High-dose FOLFIRI has an acceptable safety profile and promising efficacy. UDP-glucuronosyltransferase: (UGT1A1) polymorphism may be predictive of toxicity and efficacy of irinotecan. This phase II study aimed to evaluate the combination of high-dose FOLFIRI plus bevacizumab in patients with previously untreated metastatic colorectal cancer (MCRC) based on their UGT1A1 genotype. Patients with the UGT1A1 *1/*1 (group 1) or *1/*28 (group 2) genotype received bevacizumab plus high-dose FOLFIRI every 2 weeks. Using the Bryant and Day design with objective response rate and toxicity as the primary endpoints, 54 patients in each group were required with a planned interim analysis after inclusion of 17 patients per group. We planned to stop the trial at the interim analysis if ≤7 patients exhibited an objective response (OR) and/or ≥3 patients exhibited severe toxicity. At the interim analysis, ORs were higher than the number expected: 52.9% (group 1) and 58.8% (group 2). More than three toxic events occurred in both groups and, according to the interim analysis rule, the trial was closed due to unacceptable toxicity. Recruitment was stopped when 86 patients were included and an analysis on overall population was done for overall survival (OS) and progression-free survival (PFS). The median PFS was 10.7 months (group 1) and 10.4 months (group 2). The median OS was 25.5 months (group 1) and 23.9 months (group 2). This trial does not support the use of the intensive treatment with HD-FOLFIRI plus bevacizumab combination for MCRC in patients with the UGTA1*1/UGT1A1*1 or UGT1A1*1/UGT1A1*28 genotype. Mol Cancer Ther; 14(12); 2782–8. ©2015 AACR.

Feasibility of preoperative and postoperative chemoradiotherapy in gastric adenocarcinoma. Two phase II studies done in parallel. Fédération Francophone de Cancérologie Digestive 0308

BACKGROUNDnFor resectable gastric cancer, both postoperative chemoradiotherapy and perioperative chemotherapy demonstrate high-level evidence for improved survival in Western populations. To evaluate the feasibility of pre- or postoperative chemoradiotherapy, we proposed two multicentre phase II studies.nnnPATIENTS AND METHODSnPatients with localised, histologically confirmed gastric cancer and Eastern Cooperative Oncology Group (ECOG) performance status <2 judged suitable for curative resection were eligible. Eligible patients were assigned to either preoperative chemoradiotherapy followed by surgical resection or surgical resection followed by chemoradiotherapy depending on each centre. Chemoradiotherapy regimen included four courses of FOLFIRI (5 Fluorouracil, Leucovorin, Irinotecan) regimen then Concurrent fluorouracil at 200 mg/m2/d by continuous infusion 5 days each week. A dose of 50 Gy in 25 fractions in the preoperative study, or 45 Gy in 25 fractions in the postoperative study, was delivered. The primary end-point for both studies was the proportion of patients, who completed the therapeutic sequence.nnnRESULTSnBetween September 2007 and January 2010, 63 patients were included in both studies. The postoperative study was stopped for futility at the first step. In the preoperative study, 31 patients (73.8%, confidence interval (CI) 95%: 65.8-90.1%) received complete therapeutic sequence. Serum albumin and dietary restriction evaluated by QLQ-STO22 (Quality of Life-Stomach module) score were significantly linked with chemoradiotherapy feasibility in univariate analysis with respectively Odds-ratio (OR) 1.16 [CI 95%: 1.01-1.33] and 0.17 [0.03-0.89], p=0.04. Median overall survival time was 26.4 months in the preoperative study.nnnCONCLUSIONnFeasibility of chemoradiotherapy was not achieved for these studies: 73.8% (CI 95%: 65.8-90.1) and 42.9% (CI 95%: 21.8-66%) in preoperative and postoperative settings respectively.