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Port-Saint-Louis-du-Rhône, France

Innominato P.F.,French Institute of Health and Medical Research | Innominato P.F.,S0776Paris South University | Innominato P.F.,University Paris - Sud | Giacchetti S.,French Institute of Health and Medical Research | And 20 more authors.
Cancer | Year: 2013

BACKGROUND Chemotherapy-induced neutropenia has been associated with prolonged survival selectively in patients on a conventional schedule (combined 5-fluorouracil, leucovorin, and oxaliplatin [FOLFOX2]) but not on a chronomodulated schedule of the same drugs administered at specific circadian times (chronoFLO4). The authors hypothesized that the early occurrence of chemotherapy-induced symptoms correlated with circadian disruption would selectively hinder the efficacy of chronotherapy. METHODS Fatigue and weight loss (FWL) were considered to be associated with circadian disruption based on previous data. Patients with metastatic colorectal cancer (n = 543) from an international phase 3 trial comparing FOLFOX2 with chronoFLO4 were categorized into 4 subgroups according to the occurrence of FWL or other clinically relevant toxicities during the initial 2 courses of chemotherapy. Multivariate Cox models were used to assess the role of toxicity on the time to progression (TTP) and overall survival (OS). RESULTS The proportions of patients in the 4 subgroups were comparable in both treatment arms (P =.77). No toxicity was associated with TTP or OS on FOLFOX2. The median OS on FOLFOX2 ranged from 16.4 (95% confidence limits [CL], 7.2-25.6 months) to 19.8 months (95% CL, 17.7-22.0 months) according to toxicity subgroup (P =.45). Conversely, FWL, but no other toxicity, independently predicted for significantly shorter TTP (P <.0001) and OS (P =.001) on chronoFLO4. The median OS on chronoFLO4 was 13.8 months (95% CL, 10.4-17.2 months) or 21.1 months (95% CL, 19.0-23.1 months) according to presence or absence of chemotherapy-induced FWL, respectively. CONCLUSIONS Early onset chemotherapy-induced FWL was an independent predictor of poor TTP and OS only on chronotherapy. Dynamic monitoring to detect early chemotherapy-induced circadian disruption could allow the optimization of rapid chronotherapy and concomitant improvements in safety and efficacy. © 2013 American Cancer Society.

Hindie E.,University Paris Diderot | Groheux D.,University Paris Diderot | Brenot-Rossi I.,Institute Paoli Calmettes | Rubello D.,Nuclear Medicine PET Unit | And 2 more authors.
Journal of Nuclear Medicine | Year: 2011

Axillary node status is a major prognostic factor in early breast cancer. Staging with sentinel node biopsy (SNB) leads to a substantial reduction in surgical morbidity. Recent multiinstitutional studies revealed SNB false-negative rates ranging from 5.5% to 16.7%, higher than the target (<5%) set by the 2005 guidelines of the American Society of Clinical Oncology. These alarming data point to the necessity of optimization. Dual mapping with radiotracer and blue dye, combining 2 different injection sites, and routinely using lymphoscintigraphy may improve accuracy. Factors associated with decreased sensitivity, such as prior excisional biopsy or neoadjuvant chemotherapy, should be recognized. The use of SNB in situations with a high prevalence of node positivity (large tumor, multifocality) is controversial. The risk of missed disease after negative SNB ranges from 1% to 4% in patients with T1 tumor and up to 15% in patients with T3. With peritumoral injection, internal mammary drainage is seen in about 20% of cases. Patients combining internal mammary drainage with a positive axillary sentinel node have close to a 50% probability of internal mammary involvement. Lymphoscintigraphy might thus be helpful in selecting patients for whom internal mammary radiation has a high benefit-to-risk ratio. Copyright © 2011 by the Society of Nuclear Medicine, Inc.

Hatt M.,French Institute of Health and Medical Research | Groheux D.,Saint Louis Hospital | Groheux D.,University Paris Diderot | Martineau A.,Saint Louis Hospital | And 6 more authors.
Journal of Nuclear Medicine | Year: 2013

The goal of this study was to determine the best predictive factor among image-derived parameters extracted from sequential 18F-FDG PET scans for early tumor response prediction after 2 cycles of neoadjuvant chemotherapy in breast cancer. Methods: 51 breast cancer patients were included. Responder and nonresponder status was determined by histopathologic examination according to the tumor and node Sataloff scale. PET indices (maximum and mean standardized uptake value [SUV], metabolically active tumor volume, and total lesion glycolysis [TLG]), at baseline and their variation (D) after 2 cycles of neoadjuvant chemotherapy were extracted from the PET images. Their predictive value was investigated using Mann-Whitney U tests and receiver-operating- characteristic analysis. Subgroup analysis was also performed by considering estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative, triple-negative, and HER2-positive tumors separately. The impact of partial-volume correction was also investigated using an iterative deconvolution algorithm. Results: There were 24 pathologic nonresponders and 27 responders. None of the baseline PET parameters was correlated with response. After 2 neoadjuvant chemotherapy cycles, the reduction of each parameter was significantly associated with response, the best prediction of response being obtained with δTLG (96% sensitivity, 92% specificity, and 94% accuracy), which had a significantly higher area under the curve (0.91 vs. 0.82, P = 0.01) than did δSUVmax (63% sensitivity, 92% specificity, and 77% accuracy). Subgroup analysis confirmed a significantly higher accuracy for δTLG than δSUV for ER-positive/HER-negative but not for triple-negative and HER2-positive tumors. Partial-volume correction had no impact on the predictive value of any of the PET image-derived parameters despite significant changes in their absolute values. Conclusion: Our results suggest that the reduction after 2 neoadjuvant chemotherapy cycles of the metabolically active volume of primary tumor measurements such as δTLG predicts histopathologic tumor response with higher accuracy than does δSUV measurements, especially for ER-positive/HER2-negative breast cancer. These results should be confirmed in a larger group of patients as they may potentially increase the clinical value and efficiency of 18F-FDG PET for early prediction of response to neoadjuvant chemotherapy. COPYRIGHT © 2013 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Hindie E.,University Paris Diderot | Hindie E.,University of Bordeaux Segalen | Groheux D.,University Paris Diderot | Hennequin C.,Saint Louis Hospital | And 7 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2012

Purpose: Given the risk of undesired toxicity, prophylactic internal mammary (IM) chain irradiation should be offered only to patients at high risk of occult involvement. Lymphoscintigraphy for axillary sentinel node biopsy might help in selecting these patients. Methods and Materials: We reviewed published studies with the following selection criteria: ≥300 breast cancer patients referred for axilla sentinel node biopsy; scintigraphy performed after peritumoral or intratumoral tracer injection; IM biopsy in the case of IM drainage; and axilla staged routinely independent of IM status. Results: Six prospective studies, for a total of 3,876 patients, fulfilled the inclusion criteria. Parasternal drainage was present in 792 patients (20.4%). IM biopsy was performed in 644 patients and was positive in 111 (17.2%). Of the positive IM biopsies, 40% were associated with tumors in the lateral breast quadrants. A major difference in the IM positivity rate was found according to the axilla sentinel node status. In patients with negative axilla, the IM biopsy was positive in 7.8% of cases. In patients with positive axilla, however, the IM biopsy was positive in 41% (p < .00001). Because biopsy of multiple IM hot nodes is difficult, the true risk could be even greater, probably close to 50%. Conclusions: Patients with IM drainage on lymphoscintigraphy and a positive axilla sentinel node have a high risk of occult IM involvement. These women should be considered for IM radiotherapy. © 2012 Elsevier Inc.

Groheux D.,Nuclear Medicine | Groheux D.,University Paris Diderot | Giacchetti S.,Breast Diseases Unit | Hatt M.,French Institute of Health and Medical Research | And 9 more authors.
British Journal of Cancer | Year: 2013

Background:Pathologic complete response (pCR) to neoadjuvant treatment (NAT) is associated with improved survival of patients with HER2+ breast cancer. We investigated the ability of interim positron emission tomography (PET) regarding early prediction of pathology outcomes.Methods:During 61 months, consecutive patients with locally advanced or large HER2+ breast cancer patients without distant metastases were included. All patients received NAT with four cycles of epirubicin+cyclophosphamide, followed by four cycles of docetaxel+trastuzumab. 18 F-fluorodeoxyglucose (18 F-FDG)-PET/computed tomography (CT) was performed at baseline (PET 1) and after two cycles of chemotherapy (PET 2). Maximum standardised uptake values were measured in the primary tumour as well as in the axillary lymph nodes. The correlation between pathologic response and SUV parameters (SUV max at PET 1, PET 2 and ΔSUV max) was examined with the t-test. The predictive performance regarding the identification of non-responders was evaluated using receiver operating characteristics (ROC) analysis.Results:Thirty women were prospectively included and 60 PET/CT examination performed. At baseline, 22 patients had PET+ axilla and in nine of them 18 F-FDG uptake was higher than in the primary tumour. At surgery, 14 patients (47%) showed residual tumour (non-pCR), whereas 16 (53%) reached pCR. Best prediction was obtained when considering the absolute residual SUV max value at PET 2 (AUC=0.91) vs 0.67 for SUV max at PET 1 and 0.86 for ΔSUV max. The risk of non-pCR was 92.3% in patients with any site of residual uptake >3 at PET 2, no matter whether in breast or axilla, vs 11.8% in patients with uptake ≤3 (P=0.0001). The sensitivity, specificity, PPV, NPV and overall accuracy of this cutoff were, respectively: 85.7%, 93.8%, 92.3%, 88.2% and 90%.Conclusion:The level of residual 18 F-FDG uptake after two cycles of chemotherapy predicts residual disease at completion of NAT with chemotherapy+trastuzumab with high accuracy. Because many innovative therapeutic strategies are now available (e.g., addition of a second HER2-directed therapy or an antiangiogenic), early prediction of poor response is critical. © 2013 Cancer Research UK. All rights reserved.

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