Papers by Jihane Boustani
Cancers
Background: The role of inflammation in the development and prognosis of bladder cancer (BC) is n... more Background: The role of inflammation in the development and prognosis of bladder cancer (BC) is now established. We evaluated the significance of neutrophil-to-lymphocyte ratio (NLR) and neutrophil count (PNN) in patients with localized BC treated with chemoradiation. Methods: Clinical characteristics and baseline biological data were retrospectively collected. We tested the association between NLR, PNN, and overall survival (OS) and progression-free survival (PFS). Results: One hundred and ninety-four patients were included. Median PNN was 4000.0/mm3 [1500.0–16,858.0] and median NLR was 2.6 [0.6–19.2]. In patients with NLR > 2.6, median OS and PFS were lower (OS: 25.5 vs. 58.4 months, p = 0.02; PFS: 14.1 vs. 26.7 months, p = 0.07). Patients with PNN > 4000/mm3 had significantly lower OS (21.8 vs. 70.1 months, p < 0.001) and PFS (13.7 vs. 38.8 months, p < 0.001). Contrary to NLR, PNN > 4000/mm3 was associated with shorter OS and PFS in multivariate analysis. Conclusio...
International Review of Cell and Molecular Biology
Frontiers in Oncology
BackgroundAdvanced rectal squamous cell carcinoma (rSCC) is a very rare and aggressive entity, an... more BackgroundAdvanced rectal squamous cell carcinoma (rSCC) is a very rare and aggressive entity, and the best initial management is crucial for long survival as well as organ preservation and quality of life. Whereas local diseases are treated with chemo-radiotherapy and salvage surgery, data are scarce on how to treat more advanced diseases, and the role of induction chemotherapy is unknown.MethodsWe retrospectively analyzed all consecutive patients with advanced rSCC and treated with modified DCF (docetaxel, cisplatin, 5-fluorouracil; mDCF) regimen, from January 2014 and December 2021 in two French centers. Exploratory endpoints were efficacy (overall survival, recurrence-free survival, response rate, organ preservation rate) and safety.ResultsNine patients with locally advanced or metastatic diseases received a mDCF regimen and were included for analysis. The median age was 62.0 years, 7 patients (77.8%) were women, and all eight available tumors were positive for HPV, mostly (85.7...
Advances in Radiation Oncology
Frontiers in Oncology
IntroductionThe incidence of metastatic squamous cell carcinoma of the anus (SCCA) is increasing.... more IntroductionThe incidence of metastatic squamous cell carcinoma of the anus (SCCA) is increasing. Even if systemic docetaxel, cisplatin, and 5-Fluorouracil (DCF) provide a high rate of long-term remission, the role of pelvic chemoradiation (CRT) is unknown in this setting. We reported the safety and efficacy of local CRT in patients with synchronous metastatic SCCA who achieved objective response after upfront DCF.MethodsPatients included in Epitopes HPV01 or Epitopes HPV02 or SCARCE trials and treated with DCF followed by pelvic CRT were included. Concurrent chemotherapy was based on mitomycin (MMC) (10 mg/m² for two cycles) and fluoropyrimidine (capecitabine 825 mg/m² twice a day at each RT treatment day or two cycles of intra-venous 5FU 1000 mg/m² from day 1 to day 4). Primary endpoints were safety, local complete response rate, and local progression-free survival (PFS). Secondary endpoints were PFS, overall survival (OS), and metastasis-free survival (MFS).ResultsFrom 2013 to 20...
Additional file 2: Supplementary Figure S2. Kaplan-Meier overall survival (OS) curves in patients... more Additional file 2: Supplementary Figure S2. Kaplan-Meier overall survival (OS) curves in patients according to TERT specific T-cell responses and immunosuppressive cells levels before and after CRT. OS according toTERT-specific responses levels (A), MDSC levels (B), andTreg levels (C).
Additional file 1: Supplementary Figure S1. Gating strategy for flow cytometry analyses. The figu... more Additional file 1: Supplementary Figure S1. Gating strategy for flow cytometry analyses. The figure shows the gating strategy to Treg (A) and MDSC (B) populations. Frequencies of Treg cells were observed in CD4 T-cell population. Expression of CD127, FoxP3, and CTLA4 were analyzed on Treg (A). MDSC populations were analyzed after exclusion of lineage (CD3, CD56, CD19)(B).
Additional file 3: Supplementary Table S1. List of monoclonal antibodies used for flow cytometry.
Journal of Clinical Oncology, 2022
TPS7 Background: Even though the recurrence rate remains high, chemoradiotherapy (CRT) alone is t... more TPS7 Background: Even though the recurrence rate remains high, chemoradiotherapy (CRT) alone is the standard treatment in locally advanced squamous cell anal carcinoma (SCAC), in the absence of effective neoadjuvant/adjuvant treatment. Modified docetaxel, cisplatin and 5FU (mDCF) is one of the standard regimens in metastatic SCAC, and induced a radiological complete response (cCR) in 45% of patients, with a biological CR (the conversion from positive to negative HPV ctDNA by liquid biopsy) in 61% of patients. Among chemotherapy-naïve patients, the cCR was as high as 55%, with 90% of ORR and 100% of disease control rate during the first 4 months. Moreover, mDCF was associated with a decrease in Myeloid-Derived Suppressive Cells (MDSC) and an increase in the antitumor anti-hTERT immunity, two major factors correlated with prognosis in advanced SCAC, rendering mDCF a good partner to combine with immunotherapy. Anti-PD1 immunotherapy is effective in chemorefractory SCAC. In sensitive tu...
Background: Rectal linitis plastica (RLP) is a rare disease with poor outcome. It is often accomp... more Background: Rectal linitis plastica (RLP) is a rare disease with poor outcome. It is often accompanied by a delayed histo-pathological diagnosis, primarily due to submucosal disease. A concentric ring pattern or “target sign ” on T2-weighted magnetic resonance imaging (MRI) has been proposed as being characteristic for early suspicion. Even though RLP is more aggressive and has poorer survival than other rectal adenocarcinomas, no specific treatment is recommended. In this case report of 3 patients, we challenge the sensitivity of the characteristic radiological pattern, and we review the existing data for a treatment strategy. Case Report: One patient presented classic clinical characteristics of RLP with young age and advanced stage at diagnosis, with chemo-refractory disease and rapid fatal evolution. Biopsies confirmed the RLP with the presence of sig-net-ring cells (SRC) in a strong desmoplastic stromal reaction. However, the characteristic concentric ring pat-tern was absent. ...
Cancers, 2021
Squamous cell carcinoma of the anus is an orphan disease, and after more than three decades of no... more Squamous cell carcinoma of the anus is an orphan disease, and after more than three decades of no substantial advances in disease knowledge and treatment, it is finally gaining momentum with the arrival of a taxane-based chemotherapy and immunotherapy. Currently, about 20 combination clinical trials with an anti-PD1/L1 are ongoing in localized and advanced stages, in association with radiotherapy, chemotherapy, tumor vaccines, anti-CTLA4, anti-EGFR, or antiangiogenic molecules. Moreover, a new biomarker with high sensitivity and specificity such as HPV circulating tumor DNA (HPV ctDNA) by liquid biopsy, is improving not only the prognostic measurement but also the treatment strategy guidance for this disease. Finally, better understanding of potential targets is reshaping the present and future clinical research in this unique, HPV genotype-16-related disease in the great majority of patients.
BMC Immunology, 2021
Background The synergistic effect of chemoradiation (CRT) has been previously demonstrated in sev... more Background The synergistic effect of chemoradiation (CRT) has been previously demonstrated in several cancer types. Here, we investigated the systemic immune effects of CRT in patients with lung or head and neck cancer. Materials and methods Peripheral blood mononuclear cells were collected at baseline and 1 month after treatment from blood samples of 29 patients treated with cisplatin-based chemoradiotherapy for lung or head and neck cancer. Circulating anti-tumor Th1 response was assessed by the ELISpot assay using a mixture of human leucocyte antigen (HLA) class II restricted peptides derived from telomerase (TERT). Phenotyping of circulating immunosuppressive cells (Treg and MDSC) was performed by flow cytometry. Results A significant increase of circulating Treg was observed in 60% of patients after CRT The mean rate of Treg was 3.1% versus 4.9% at baseline and after CRT respectively, p = 0.0015). However, there was a no significant increase of MDSC rate after CRT. In contrast,...
International Journal of Radiation Oncology*Biology*Physics, 2021
PURPOSE/OBJECTIVE(S) Increasing dose of chemoradiotherapy in locally advanced esophageal cancer u... more PURPOSE/OBJECTIVE(S) Increasing dose of chemoradiotherapy in locally advanced esophageal cancer unsuitable for surgery has been a matter of debate in the last 2 decades. Advances in tumor staging and radiation targeting with modern imaging and IMRT should allow further testing exclusive radiation dose escalation in esophageal cancer. MATERIALS/METHODS We performed a multicenter, randomized, open-label, parallel-group, phase 2/3 trial of patients aged 18 years or older enrolled from 28 centers in France between 07/06/2011 and 11/10/2019. Eligible participants had confirmed stage I-III biopsy proven esophageal carcinoma, ECOG 0-2 and sufficient caloric intake. Patients were randomly assigned (1:1) to receive 50Gy in 25 fractions over 5 weeks (standard arm) or 66Gy in 33 fractions over 6.5 weeks (experimental arm). Elective nodal irradiation (40Gy) was delivered in both groups. Concomitant chemotherapy was FOLFOX-4 for 3 courses followed by 3 adjuvant courses. Random allocation to treatment groups was done by a central computerized randomization procedure by minimization, stratified by center, histology, weight loss, and technique of radiotherapy. The primary endpoint was 2-year locoregional progression-free survival (LRPFS). RESULTS 109 participants were randomly allocated to the 50Gy arm and 108 to the 66Gy group (intention-to-treat population). 177 men (81.6%) and 40 women (18.4%) were included with a mean age of 62.6 years (± 7.8). 191 patients (88.4%) had squamous cell cancer and 25 (11.6%) has adenocarcinoma. Most of the patients had stage III tumors (74% vs 26% for stage I-II). IMRT was delivered in 169 patients (80.1%) and 3D conformal in 42 patients (19.9%). 59 patients (54.1%) have died in the 50Gy group and 65 patients (60.2%) in the 66Gy group with a median follow up 35.3 months (range: 2.0-65.7) and 35.5 months (range: 1.3-60.7), respectively. Median overall survival was 25.2 months (95% CI 17.8-NR) in the 50Gy group and 23.5 months (14.5-32.2) in the 66Gy group (HR 1.14, 95% CI 0.82-1.59; P = 0.44). Median LRPFS was 16.2 months (95% CI 10.9-26.0) in the 50Gy group and 18.4 months (12.2-25.7) in the 66Gy group (HR 1.03, 95% CI 0.75-1.40; P = 0.88). The 2-year LRPFS rates were 42.7% (95% CI 33.2%-51.8%) and 43.8% (95% CI 34.1%-54.1%). No significant differences were recorded in the rates of late adverse events between the treatment groups (P = 0.14). The rates of grade 3/4 toxicities in the 50Gy group were 29.5%/0% and 24.0%/5.3% in the 66Gy group. 5 toxic deaths (4.6%) occurred in the 50Gy group and 7 (6.7%) in the 66Gy group. One and 2 toxic deaths out of the 5 in the 50Gy were related to radiotherapy or chemotherapy, respectively. Two and 3 out of the 7 toxic deaths in the 66Gy were related to radiotherapy or chemotherapy, respectively. CONCLUSION Dose escalated chemoradiotherapy delivering 66Gy is not more toxic than 50Gy but did not improve locoregional progression-free survival. Chemoradiotherapy delivering 50Gy should be definitely admitted as a standard dose.
Cancers, 2021
Immune checkpoint inhibitors have been associated with long-term complete responses leading to im... more Immune checkpoint inhibitors have been associated with long-term complete responses leading to improved overall survival in several cancer types. However, these novel immunotherapies are only effective in a small proportion of patients, and therapeutic resistance represents a major limitation in clinical practice. As with chemotherapy, there is substantial evidence that radiation therapy promotes anti-tumor immune responses that can enhance systemic responses to immune checkpoint inhibitors. In this review, we discuss the main preclinical and clinical evidence on strategies that can lead to an enhanced response to PD-1/PD-L1 blockade in combination with radiation therapy. We focused on central issues in optimizing radiation therapy, such as the optimal dose and fractionation for improving the therapeutic ratio, as well as the impact on immune and clinical responses of dose rate, target volume, lymph nodes irradiation, and type of radiation particle. We explored the addition of a thi...
Journal for ImmunoTherapy of Cancer, 2021
BackgroundMultiple synergistic combination approaches with cancer drugs are developed to overcome... more BackgroundMultiple synergistic combination approaches with cancer drugs are developed to overcome primary resistance to immunotherapy; however, the mechanistic rationale to combine chemoradiotherapy (CRT) with immune checkpoint inhibitors remains elusive.MethodsThis study described the immunological landscape of tumor microenvironment (TME) exposed to CRT. Tumor samples from patients with rectal cancer (n=43) treated with neoadjuvant CRT or radiotherapy were analyzed by nanostring and immunohistochemistry. Studies in mice were performed using three syngeneic tumors (TC1, CT26 and MC38). Tumor-bearing mice were treated either with platinum-based CRT, radiotherapy or chemotherapy. Anti-CTLA-4 and/or anti-Programmed Cell Death Receptor-1 (PD-1) therapy was used in combination with CRT. The therapy-exposed TME was screened by RNA sequencing and flow cytometry and tumor-infiltrating T lymphocyte functionality was evaluated by interferon (IFN)-γ ELIspot and intracellular cytokine staining...
Radiotherapy and Oncology, 2021
Cells, 2020
In locally advanced rectal cancer, radiotherapy (RT) followed by surgery have improved locoregion... more In locally advanced rectal cancer, radiotherapy (RT) followed by surgery have improved locoregional control, but distant recurrences remain frequent. Although checkpoint inhibitors have demonstrated objective response in several cancers, the clinical benefit of PD-1/PD-L1 blockade remains uncertain in rectal cancer. We collected data from biopsies and surgical specimens in 74 patients. The main objective was to evaluate the impact of neoadjuvant RT and fractionation on PD-L1 expression. Secondary objectives were to study the relation between PD-L1 expression and tumor regression grade (TRG), progression-free survival (PFS), overall survival (OS), and CD8 TILs infiltration. Median rates of cells expressing PD-L1 pre- and post-RT were 0.15 (range, 0–17) and 0.5 (range, 0–27.5), respectively (p = 0.0005). There was no effect of RT fractionation on PD-L1+ cell rates. We found no relation between CD8+ TILs infiltration and PD-L1 expression and no difference between high-PD-L1 or low-PD-L...
International Journal of Radiation Oncology*Biology*Physics, 2019
We performed a benchmark case procedure as part of a quality assurance procedure of the ongoing P... more We performed a benchmark case procedure as part of a quality assurance procedure of the ongoing PRODIGE 26/CONCORDE trial assessing dose-escalated radiation therapy in esophageal cancer. Inconsistencies in delineating target and organat-risk volumes were found. Only one-third of the plans were protocol compliant. The majority of deviations were minor and involved the Purpose: The ongoing phase 2/3 PRODIGE 26/CONCORDE trial compares chemoradiation therapy with and without dose escalation in patients with locally advanced or unresectable esophageal cancer. The results of a benchmark case procedure are reported here to evaluate the protocol compliance of participating centers as part of quality assurance for radiation therapy. Methods and Materials: Volume delineation, target coverage, and dose constraints to the organs at risk (OARs) were assessed on treatment plans of a common benchmark case performed by each participating center. The centers were classified in 3 categories: per protocol, minor acceptable deviation (MiD), or major unacceptable deviation (MaD). A plan was rejected if !4 MiDs or 1 MaD were found. Results: Thirty-5 centers submitted 43 plans. Among them, 14 (32.6%) were per protocol, 19 (44.2%) presented at least 1 MiD, 2 (4.6%) presented at least 1 MaD, and 8 (18.6%) presented both MiD and MaD. Overall, 11 (25.6%) plans were rejected. Only 1 plan was rejected because gross tumor volume was not correctly delineated. The OAR delineation was respected in all cases. Dose constraints to the OARs were
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Papers by Jihane Boustani