Fabrice Denis

Improving Survival in Patients Treated for a Lung Cancer Using Self-evaluated Symptoms Reported Through a Web Application

Objectives: We retrospectively compared survivals in patients with a lung cancer history and followed by the so-called sentinel Web-application that allows early detection of relapse and early palliative care initiation versus a conventional follow-up in our center. Methods: The survival in 98 consecutive patients with lung cancer was assessed. The first part of them (the control arm) was retrospectively recruited between March 2011 and August 2012. The second half of them (the experimental arm) was prospectively recruited between August 2012 and December 2013 to weekly fill a form of 11 self-assessed symptoms, then processed by the “sentinel” Web-application. Data were sent to this sentinel application in real-time between planned visits. An email alert was sent to the oncologist when self-scored symptoms matched some predefined criteria. Follow-up visit and imaging were then organized after a phone call for confirming the suspect symptoms. In the control arm (49 patients), a common follow-up was applied (visit and imaging every 2 to 6 mo according to stage of tumor and kind of treatment). Results: Median follow-up duration was 12.3 months in the experimental arm and 16.7 months in the control arm (P=0.27). Survival was significantly better in the sentinel arm than in the control arm (P=0.0014). Median survival was 16.7 months in the control arm and 22.4 months in the experimental arm. One-year survival was 86.6% in the experimental arm and 59.1% in the control arm. Conclusions: Survival may be improved by early detection of relapse and early palliative care initiation by using sentinel-like Web-application.

Phase II Study of a Radiotherapy Total Dose Increase in Hypoxic Lesions Identified by 18 F-Misonidazole PET/CT in Patients with Non–Small Cell Lung Carcinoma (RTEP5 Study)

See an invited perspective on this article on page 1043. This multicenter phase II study investigated a selective radiotherapy dose increase to tumor areas with significant 18F-misonidazole (18F-FMISO) uptake in patients with non–small cell lung carcinoma (NSCLC). Methods: Eligible patients had locally advanced NSCLC and no contraindication to concomitant chemoradiotherapy. The 18F-FMISO uptake on PET/CT was assessed by trained experts. If there was no uptake, 66 Gy were delivered. In 18F-FMISO–positive patients, the contours of the hypoxic area were transferred to the radiation oncologist. It was necessary for the radiotherapy dose to be as high as possible while fulfilling dose-limiting constraints for the spinal cord and lungs. The primary endpoint was tumor response (complete response plus partial response) at 3 mo. The secondary endpoints were toxicity, disease-free survival (DFS), and overall survival at 1 y. The target sample size was set to demonstrate a response rate of 40% or more (bilateral α = 0.05, power 1-β = 0.95). Results: Seventy-nine patients were preincluded, 54 were included, and 34 were 18F-FMISO–positive, 24 of whom received escalated doses of up to 86 Gy. The response rate at 3 mo was 31 of 54 (57%; 95% confidence interval [CI], 43%–71%) using RECIST 1.1 (17/34 responders in the 18F-FMISO–positive group). DFS and overall survival at 1 y were 0.86 (95% CI, 0.77–0.96) and 0.63 (95% CI, 0.49–0.74), respectively. DFS was longer in the 18F-FMISO–negative patients (P = 0.004). The radiotherapy dose was not associated with DFS when adjusting for the 18F-FMISO status. One toxic death (66 Gy) and 1 case of grade 4 pneumonitis (>66 Gy) were reported. Conclusion: Our approach results in a response rate of 40% or more, with acceptable toxicity. 18F-FMISO uptake in NSCLC patients is strongly associated with poor prognosis features that could not be reversed by radiotherapy doses up to 86 Gy.

A cancer model for the angiogenic switch

The occurrence of metastasis is an important feature in cancer development. In order to have a one-site model taking into account the interactions between host, effector immune and tumor cells which is not only valid for the early stages of tumor growth, we developed in this paper a new model where are incorporated interactions of these three cell populations with endothelial cells. These latter cells are responsible for the neo-vascularization of the tumor site which allows the migration of tumor cells to distant sites. It is then shown that, for some parameter values, the resulting model for the four cell populations reproduces the angiogenic switch, that is, the transition from avascular to vascular tumor.

How tumor growth can be influenced by delayed interactions between cancer cells and the microenvironment

Although recent advances in oncology emphasized the role of microenvironment in tumor growth, the role of delays for modeling tumor growth is still uncertain. In this paper, we considered a model, describing the interactions of tumor cells with their microenvironment made of immune cells and host cells, in which we inserted, as suggested by the clinicians, two time delays, one in the interactions between tumor cells and immune cells and, one in the action of immune cells on tumor cells. We showed analytically that the singular point associated with the co-existence of the three cell populations loses its stability via a Hopf bifurcation. We analytically calculated a range of the delays over which tumor cells are inhibited by immune cells and over which a period-1 limit cycle induced by this Hopf bifurcation is observed. By using a global modeling technique, we investigated how the dynamics observed with two delays can be reproduced by a similar model without delays. The effects of these two delays were thus interpreted in terms of interactions between the cell populations.

Spatial avascular growth of tumor in a homogeneous environment

Describing tumor growth is a key issue in oncology for correctly understanding the underlying mechanisms leading to deleterious cancers. In order to take into account the micro-environment in tumor growth, we used a model describing - at the tissue level - the interactions between host (non malignant), effector immune and tumor cells to simulate the evolution of cancer. The spatial growth is described by a Laplacian operator for the diffusion of tumor cells. We investigated how the evolution of the tumor diameter is related to the dynamics (periodic or chaotic oscillations, stable singular points) underlying the interactions between the different populations of cells in proliferation sites. The sensitivity of this evolution to the key parameter responsible for the immuno-evasion, namely the growth rate of effector immune cells and their inhibition rate by tumor cells, is also investigated.

Use of Metabolic Parameters as Prognostic Factors During Concomitant Chemoradiotherapy for Locally Advanced Cervical Cancer

Objectives: To investigate the use of metabolic parameters as early prognostic factors during concomitant chemoradiotherapy for locally advanced cervix carcinoma (LACC). Materials and Methods: Between February 2008 and January 2012, 34 consecutive patients treated for LACC (International Federation of Gynecology and Obstetrics Staging System stage IB2-IVA) were included in a retrospective study. Treatment was standard of care: total dose of 45 Gy in 1.8 Gy per fraction with concurrent cisplatin followed by brachytherapy. 18F-FDG PET-CT modalities were performed before treatment and per-treatment (at 40 Gy). The analyzed parameters were: maximum standardized uptake value (SUVmax), SUVmax variations of the primary tumor between the 2 investigations (DSUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG). Survival was assessed according to early metabolic changes during chemoradiotherapy. Results: Median follow-up was 16 months (range, 5.3 to 32.4 mo). Median SUVmax before treatment was 13.15 (5.9 to 31) and was 5.05 (0 to 12) per-treatment. Median DSUVmax was 63.97% (0% to 100%). Median MTV before treatment was 44.16 mL (3.392 to 252.768 mL) and was 5.44 mL (0 to 69.88 mL) per-treatment. Median TLG before treatment was 249.82 mL (13.40 to 1931.10 mL) and was 20.14 mL (0 to 349.99 mL) per-treatment. At 40 Gy, SUVmax≥6, DSUVmax⩽40%, MTV≥5.6 mL, and TLG≥21.6 mL were significantly associated with overall survival and progression-free survival reduction. MTV predicted progression with a sensitivity of 80% and a specificity of 87.5% and TLG with a sensitivity of 80% and a specificity of 83.3%. Conclusions: PET-CT imaging could be useful as an early prognostic factor during treatment for LACC. MTV and TLG seem to provide better prognostic information than SUVmax and DSUVmax.

Abstract 3760: Modeling spatial tumor growth as seen in clinical and radiological observations

Aim: Predicting tumour growth is a key issue in oncology for which correctly understanding underlying mechanisms is required. In order to do that, we developed a spatio-temporal mathematical model at tissue level for tumorigenesis. Our model is based on a set of four differential equations describing interactions between host, immune, tumour and endothelial cells that we recently developed for a single site. This model is spontaneously able to reproduce angiogenic switch and metastatic phenotype. Method: The present work is devoted to an extension onto a spatial two-dimensional Euclidean grid in which each site corresponds to approximatively ten thousand square micrometers and contains about one hundred cells. Only tumour cells can diffuse from one site to one of its eight nearest neighbors, thus corresponding to a partial differential equation with an isotropic Laplacian operator for tumour cell diffusion. Initial conditions are such as a single site located in the center of the grid contains tumour cells (all the other are tumour cells free). The tumour growth is thus obtained by integrating the differential equations using a fourth-order Runge-Kutta scheme. Results: Since we explicitly considered endothelial cells, our simulations can reproduce avascular as well as vascular tumour growth. We thus obtained round tumour until its diameter reaches two millimeters. Larger tumours are progressively deformed according to the nutrient gradient in the tissue: quiescent and necrotic zones are thus obtained as a function of tumour radius and micro-environment. Shaping our grid for reproducing lung anatomic, we were able to reproduce tumour growth constrained by the presence of anatomical structures such as bronchi. Conclusion: The structure of the so-obtained tumour is equivalent to those observed in patient using diagnosis imaging; our spatio-temporal model for tumour growth thus provides tumour growth in agreement with clinical and radiological observations. Citation Format: Louise Viger, Clement Draghi, Fabrice Denis, Christophe Letellier. Modeling spatial tumor growth as seen in clinical and radiological observations. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3760. doi:10.1158/1538-7445.AM2015-3760

Response to Andrea Tendas et al.’s making quality of life assessment a dashboard for patients management

To the Editor, We have read with great interest the letter by Tendas A et al. about our paper “Detecting lung cancer relapse using selfevaluation forms weekly filled at home: the sentinel followup,” which introduced a new modality of lung cancer relapse monitoring through the use of a weekly self-evaluation of six symptoms closely related to the disease. Our colleague suggests to assess prospectively which symptoms should be assessed, how often and how long to monitor symptoms allowing early detection of relapse and early supportive care. In our last paper in the SCC journal, we assessed a weekly monitoring of 11 self-assessed symptoms and the use of a web-application that sent data to an oncologist in real-time and triggered alerts according to symptom dynamics and association. Weekly and monthly average compliances were 79 and 94 %, respectively [1]. Sixty percent of patients declared to be less anxious during the few days before planned visit and imaging with the sentinel follow-up than without. They told that they were ready to use this application for 2 years or more. Sensitivity, specificity, positive, and negative predictive values provided by the sentinel (planned imaging) follow-up were 100 % (84%), 89% (96 %), 81% (91%), and 100 % (93 %), respectively, and well correlated with relapse (pχ<0.001). On average, relapses were detectable 5 weeks earlier with sentinel than planned visit, and supportive cares were triggered earlier than without such application. Overall survival seemed improved versus standard follow-up in a nonrandomized assessment (data not yet published). We thus decided to perform a multicenter phase 3 randomized trial comparing sentinel follow-up to standard follow-up of patients with nonprogressive lung carcinoma. In this study, overall survival, QOL, and cost-effectiveness will be accurately evaluated.We are processing other web-applications for the follow-up of other cancers such as breast, prostate, cervix, and colorectal cancers.