Aurélie Bertaut

Prognostic value of chemotherapy-induced hematological toxicity in metastatic colorectal cancer patients

AIM To establish whether chemotherapy-induced neutropenia is predictive of better outcome in patients with metastatic colorectal cancer (mCRC). METHODS Survival and patient characteristics from consecutive mCRC patients treated in the Centre Georges Francois Leclerc, Dijon, France between January 2001 and December 2011 were analyzed. Patient and tumor characteristics, hematological toxicity (neutropenia, anemia, and thrombocytopenia), and type of chemotherapy received were recorded. RESULTS We retrospectively analyzed data from 399 consecutive patients with mCRC who received at least one line of chemotherapy. Median follow up was 6.3 years. Eighty-eight percent of the patients received more than two lines of chemotherapy. By univariate analysis, whatever their grade, neutropenia and thrombocytopenia occurring during the first two lines of chemotherapy were significantly associated with better overall survival (HR = 0.55, 95%CI: 0.43-0.70, P < 0.0001 and HR = 0.70, 95%CI: 0.56-0.88, P = 0.025 respectively). In contrast, anemia during chemotherapy was significantly associated with poorer overall survival (HR = 1.9, 95%CI: 1.22-2.97, P = 0.005). Multivariate analysis revealed that both neutropenia and thrombocytopenia were significantly associated with better overall survival: HR = 0.43, 95%CI: 0.29-0.64, P < 0.0001 and HR = 0.69, 95%CI: 0.49-0.98, P = 0.036, respectively. CONCLUSION These data suggest that occurrence of neutropenia or thrombocytopenia during first- or second-line chemotherapy for mCRC is associated with better survival.

Immune classifications with cytotoxic CD8+ and Th17 infiltrates are predictors of clinical prognosis in glioblastoma

ABSTRACT Background: Interest is growing on immune cells involvement in central nervous system tumors such as glioblastoma. Even if a few reports highlighted that immune classifications could have a prognostic value, no paradigm has been clearly yet established on large and homogeneous cohorts. The aim of our study was to analyze the prognostic role of the in situ immune response of cytotoxic T cells (i.e., CD8+), Foxp3 cells, Th17 and tumor-associated macrophages in glioblastoma on two independent large and homogeneous cohorts. Methods: We worked on two large homogenous cohorts of patients having glioblastoma who underwent standard radiochemotherapy. The first cohort of 186 patients was analyzed using IHC procedures (CD8+, IL-17A, FoxP3 and CD163) of surgery pieces. We next worked with transcriptomic data available online and used metagene strategy analysis for the second cohort of 525 patients. Results: Cytotoxic CD8+ lymphocytes and Foxp3 cells were associated with a good prognosis, while Th17 were associated with a poor clinical outcome. These data were confirmed with transcriptomic analysis. Moreover, we showed for the first time a strong link between angiogenesis and Th17 metagenes expressions in glioblastoma. Conclusions: Our study shows that glioblastoma bearing patients can be classified on the immune infiltrate aspects. Beyond this prognostic role of immune biomarkers, subsequent classifications could definitely help clinicians to handle targeted therapy administration and immunotherapeutic interventions.

Folfirinox in elderly patients with pancreatic or colorectal cancer-tolerance and efficacy

AIM To study the tolerance and the efficiency of FOLFIRINOX in elderly patients diagnosed with colorectal or pancreatic cancer. METHODS This retrospective study included elderly patients aged over 70 years of age treated at Georges-Francois Leclerc Center by FOLFIRINOX for histological proved colorectal or pancreatic cancer between January 2009 and January 2015. Chemotheapy regimen consisted of oxaliplatin (85 mg/m2 in over 120 min) followed by leucovorin (400 mg/m2 in over 120 min), with the addition, after 30 min of irinotecan (180 mg/m2 in over 90 min) then 5 fluorouracil (5FU) (400 mg/m2 administred intravenous bolus), followed by 5FU (2400 mg/m2 intraveinous infusion over 46 h) repeated every 2 wk. Geriatric parameters were recorded at the beginning. Toxicities were evaluated with the Common Terminology Criteria for Adverse Events 4.03. Tumor response was evaluated by CT scan. Treatment continued until disease progression, unacceptable toxicities or patient refusal. RESULTS Fifty-two patients aged from 70 to 87 years were treated by FOLFIRINOX, 34 had colorectal cancer and 18 had pancreatic cancer. Most of them were in good general condition, 82.7% had a 0-1 performance status and 61.5% had a Charlson Comorbidity Index < 10. The most frequent severe toxicities were neutropenia (17 patients, n = 32.7%) and diarrhea (35 patients n = 67.3%); 10 of the case of neutropenia and 5 of diarrhea registered a grade 4 toxicity. Thirty-nine patients (75%) initially received an adapted dose of chemotherapy. The dosage was adjusted for 26% of patients during the course of treatment. Tumor response evaluated by RECIST criteria showed a controlled disease for 25 patients (48.1%), a stable disease for 13 and a partial response for 12 patients. Time under treatment was higher for colorectal cancer with a median time of 2.44 mo (95%CI: 1.61-3.25). Overall survival was 43.88 mo for colorectal cancer and 12.51 mo for pancreatic cancer. In univariate or multivariate analysis, none of geriatric parameters were linked to overall survival. Only the type of tumor (pancreatic/colorectal) was linked in both analysis. CONCLUSION For people over 70 years old, FOLFIRINOX regimen seems to induce manageable toxicities but similar, even higher, median survival rates compared to younger people.

Blood baseline neutrophil count predicts bevacizumab efficacy in glioblastoma

Bevacizumab is used to treat glioblastoma; however, no current biomarker predicts its efficacy. We used an exploratory cohort of patients treated with the radiochemotherapy then bevacizumab or chemotherapy at recurrence (N = 265). Bevacizumab use increased median overall survival (OS) 18.7 vs 11.3 months, p = 0.0014). In multivariate analysis, age, initial surgery, neutrophil count, Karnofsky status >70% and bevacizumab administration were independent prognostic factors of survival. We found an interaction between bevacizumab use and baseline neutrophil count. The cut-off value for the neutrophil count was set at 6000/mm3. Only patients with a high neutrophil count benefited from the bevacizumab treatment (17.3 vs 8.8 months p < 0.0001). We validated this result using data from the TEMAVIR trial, which tested the efficacy of neoadjuvant bevacizumab plus irinotecan versus radiochemotherapy in the first-line treatment of glioblastoma. Transcriptomic data from TCGA underlined that CSF3 expression, the gene encoding G-CSF, the growth factor for neutrophils, correlated with VEGF-A-dependent angiogenesis. In another independent cohort (BELOB trial), which compared lomustine versus lomustine plus bevacizumab at recurrence, bevacizumab only benefited patients with high CSF3 expression in the tumor. These data suggest that only patients with a high peripheral neutrophil count before bevacizumab treatment benefited from this therapy.

Selective arterial embolization of symptomatic and asymptomatic renal angiomyolipomas: a retrospective study of safety, outcomes and tumor size reduction

BACKGROUND Angiomyolipoma (AML) is the most common renal benign tumor. Treatment should be considered for symptomatic patients or for those at risk for complications, especially retroperitoneal bleeding which is correlated to tumor size, grade of the angiogenic component and to the presence of tuberous sclerosis complex (TSC). This study reports our single-center experience with the use of selective arterial embolization (SAE) in the management of symptomatic and asymptomatic renal AMLs. METHODS In this retrospective mono-centric study, all demographic and imaging data, medical records, angiographic features, outpatient charts and follow-up visits of patients who underwent prophylactic or emergency SAE for AMLs between January 2005 and July 2016 were reviewed. Tumor size and treatment outcomes were assessed at baseline and after the procedure during follow-up. Computed tomography (CT), magnetic resonance imaging (MRI) or ultrasonography was used to evaluate AML shrinkage. Renal function was measured pre- and post-procedure. RESULTS Twenty-three patients (18 females, 5 males; median age, 45 years; range, 19-85 years) who underwent SAE either to treat bleeding AML (n=6) or as a prophylactic treatment (n=17) were included. Overall, 34 AMLs were embolized. TSC status was confirmed for 6 patients. Immediate technical success rate was 96% and 4 patients benefitted from an additional procedure. Major complications occurred in 3 patients and minor post-embolization syndrome (PES) in 14 patients. The mean AML size reduction rate was 26.2% after a mean follow-up was 20.5 months (range, 0.5-56 months), and only non-TSC status was significantly associated with better shrinkage of tumor (P=0.022). Intralesional aneurysms were significantly more frequent in patients with hemorrhagic presentation (P=0.008). There was no change in mean creatinine level after SAE. CONCLUSIONS SAE is a safe and effective technique to manage renal AMLs as a preventive treatment as well as in emergency setting, with significant reduction in tumor size during follow-up. A multidisciplinary approach remains fundamental, especially for TSC patients. In addition to size, the presence of intralesional aneurysms should be considered in any prophylactic treatment decision.

Multiparametric MRI and post implant CT-based dosimetry after prostate brachytherapy with iodine seeds: The higher the dose to the dominant index lesion, the lower the PSA bounce

PURPOSE To determine whether post-implant MRI-based dosimetry of the Dominant Intra-prostatic Lesion (DIL) could best predict the occurrence of PSA bounce after prostate brachytherapy. METHODS AND MATERIALS We selected 66 patients with a low risk prostate cancer treated with (125)I prostate brachytherapy as monotherapy. Post-implant dosimetry based on day 30 CT-scan and multiparametric MRI co-registration was generated: planned D90, D95, V100, V150 values were calculated for each DIL. Bounce was defined as a PSA elevation ⩾ 0.2 ng/mL from the previous baseline value followed by a decrease to or below the prior nadir with no additional treatment. RESULTS After a median follow-up of 35.5 months (range 13.2-72.5), a PSA bounce occurred in 24 (36.4%) patients. The mean planned D90 of the DIL was significantly lower in bouncers: 196 ± 61 Gy vs. 234 ± 62 Gy, p = 0.018. The mean planned V150 of the DIL was 56 ± 32% for bouncers while it was 75 ± 30% for non-bouncers, p = 0.026. CONCLUSION A lower planned D90 or V150 in the DIL were predictive of PSA bounce after prostate brachytherapy. PSA bounce could be caused by delayed cell death related to sublethal damage accumulation in the tumor.

Comparison of three different embolic materials for varicocele embolization: retrospective study of tolerance, radiation and recurrence rate

BACKGROUND To evaluate pain, radiation and recurrence rates in patients undergoing varicocele embolization with three different embolic materials. METHODS Retrospective study of 182 consecutive patients who underwent transcatheter retrograde varicocele embolization from July 2011 to May 2015 with glue (Glubran(®)2) (group 1, n=63), mechanical agents (coils and/or plugs) (group 2, n=53) or a sclerosing agent (polidocanol) (group 3, n=66). Patients were asked by telephone interview to evaluate pain during embolization and at 1, 7 and 30 days using a quantitative pain scale ranging from 0 to 10. Duration of scopy, kinetic energy released per unit mass (kerma) and dose area product (DAP) were assessed as radiation parameters during embolization procedures. Recurrence rates after treatment were also evaluated. Statistical analyses were performed using parametric and non-parametric tests. RESULTS Patients in the three study groups were comparable for age, clinical indication and embolization side. No difference was noted for significant pain (pain score ≥3) during embolization and at 1, 7 and 30 days after treatment. Discomfort (pain score <3) was more frequent in group 1 than in groups 2 and 3 at 7 days after the procedure (P=0.049). No difference in discomfort was noted during embolization or at 1 and 30 days. Duration of scopy was shorter (P<0.0001) and kerma was lower (P=0.0087) in group 1 than in groups 2 and 3. DAP was lower in group 1 than in group 2 (P=0.04) but no difference was noted between groups 1 and 3, and groups 2 and 3. The recurrence rate at a mean follow-up of 24.4 months (range, 2-53 months) was significantly lower in group 1 than in the two other groups (P=0.032). CONCLUSIONS The use of Glubran(®)2 acrylic glue for varicocele embolization is safe and leads to less radiation and lower recurrence rates than is the case for other embolic materials without any more significant pain.

Tumor lymphocyte immune response to preoperative radiotherapy in locally advanced rectal cancer: The LYMPHOREC study

ABSTRACT Introduction: Some studies have suggested that baseline tumor-infiltrating-lymphocytes (TILs), such as CD8+ and FoxP3+ T-cells, may be associated with a better prognosis in colorectal cancer. We sought to investigate modulation of the immune response by preoperative radiotherapy (preopRT) and its impact on survival in locally advanced rectal cancer (LARC). Materials & Methods: We analyzed data for 237 patients with LARC who received RT. Density of TILS (CD8+ and FoxP3+) in intraepithelial (iTILs) and stromal compartments (sTILs) were evaluated from surgery pathological specimens and biopsies performed at baseline. The primary endpoint was to assess the impact of infiltration of the tumor or tumor site after preopRT on progression-free survival (PFS) and overall survival (OS). Secondary endpoints were the impact of dose fractionation scheme on TILs. Results: In univariate analysis, several factors significantly correlated (p<0.05) with PFS and/or OS (T-stage, M-stage, the delay between RT and surgery). A high level of post-treatment FoxP3+ TIL density correlated significantly with a better PFS (p = 0.007). In multivariate analysis, a decrease in the CD8+/FoxP3+ iTILs ratio after preopRT correlated with better PFS and OS (p = 0.049 and p = 0.024, respectively). More particularly, patients with a delta CD8+/FoxP3+ <−3.8 had better PFS and OS. Interestingly, the dose fractionation scheme significantly influenced the CD8+/FoxP3+ ratio after treatment (p = 0.027) with a lower ratio with hypofractionated RT (≥2 Gy). Conclusion: Patients with LARC who had a significant decrease in the CD8+/FoxP3+ ratio after preopRT were more likely to live longer. This ratio needs to be validated prospectively to guide physicians in adjuvant treatment decision-making.

Phase Ib/II trial evaluating the safety, tolerability and immunological activity of durvalumab (MEDI4736) (anti-PD-L1) plus tremelimumab (anti-CTLA-4) combined with FOLFOX in patients with metastatic colorectal cancer

Background 5-Fluorouracil plus irinotecan or oxaliplatin alone or in association with target therapy are standard first-line therapy for metastatic colorectal cancer (mCRC). Checkpoint inhibitors targeting PD-1/PD-L1 demonstrated efficacy on mCRC with microsatellite instability but remain ineffective alone in microsatellite stable tumour. 5-Fluorouracil and oxaliplatin were known to present immunogenic properties. Durvalumab (D) is a human monoclonal antibody (mAb) that inhibits binding of programmed cell death ligand 1 (PD-L1) to its receptor. Tremelimumab (T) is a mAb directed against the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). This study is designed to evaluate whether the addition of PD-L1 and CTLA-4 inhibition to oxaliplatin, fluorouracil and leucovorin (FOLFOX) increases treatment efficacy. Methods This phase II study (ClinicalTrials.gov NCT03202758) will assess the efficacy and safety of FOLFOX/D/T association in patients with mCRC (n=48). Good performance status patients (Eastern Cooperative Oncology Group <2) with untreated, RAS mutational status mCRC will be eligible. Prior adjuvant therapy is allowed provided recurrence is >6 months postcompletion. There is a safety lead in nine patients receiving FOLFOX/D/T. Assuming no safety concerns the study will go on to include 39 additional patients. Patients will receive folinic acid (400 mg/m²)/5-fluorouracil (400 mg/m² as bolus followed by 2400 mg/m2 as a 46-hour infusion)/oxaliplatin (85 mg/m2) every 14 days with D (750 mg) D1 every 14 days and T (75 mg) D1 every 28 days. After six cycles of FOLFOX only D/T will continue until disease progression, death, intolerable toxicity, or patient/investigator decision to stop. Primary endpoint is safety and efficacy according to progression-free survival (PFS); secondary endpoints include overall response rate and quality of life. Hypothesis is that a PFS of 50% at 6 months is insufficient and a PFS of 70.7% is expected (with α=10%, β=10%). Blood, plasma and tumour tissue will be collected and assessed for potential prognostic and predictive biomarkers.

Pattern of breast cancer blood flow and metabolism, assessed using dual-acquisition 18FDG PET: correlation with tumor phenotypic features and pathological response to neoadjuvant chemotherapy

Early changes in tumor glucose metabolism (SUVmax) and in tumor blood flow (BF) have been evaluated separately for monitoring breast cancer response to neoadjuvant chemotherapy (NAC). This study used a single 18F-FDG dual-acquisition PET examination to simultaneously assess these two imaging features and to determine whether they correlate with the same pretherapy tumor phenotypic features and whether they are comparable or complementary in predicting pathologic complete response (pCR). Methods: This prospective study included 150 women with breast cancer and an indication for NAC. A 2-min chest-centered dynamic PET acquisition was performed at the time of 18F-FDG injection, followed by a delayed static PET acquisition 90 min later. Tumor BF was calculated from the dynamic acquisition using a validated first-pass model, and tumor SUVmax was calculated from the delayed acquisition. This dual acquisition was repeated after the first cycle of NAC to measure early changes in tumor BF and SUVmax. Results: A weak correlation was found between SUVmax and BF at baseline (r = 0.22; P = 0.006). A high baseline SUVmax was associated with all biologic markers of tumor aggressiveness, including the triple-negative breast cancer subtype (P < 0.0001). In contrast, a high baseline BF was associated only with obesity (P = 0.002). The change in SUVmax (mean, −44.6% ± 27.4%) varied depending on the Scarff–Bloom–Richardson grade, overexpression of human epidermal growth factor receptor 2 (HER2-positive), and lack of hormone receptor expression (P = 0.04, P < 0.001, and P = 0.01, respectively). BF (mean change, −26.9% ± 54.3%) showed a drastic reduction only in HER2-positive subtypes (−58.7% ± 30.0%), supporting the antiangiogenic effect of trastuzumab. Changes in SUVmax outperformed changes in BF for predicting pCR in all tumor subtypes: the areas under the curve for change in SUVmax were 0.82, 0.65, and 0.90 in the triple-negative, HER2-positive, and luminal subtypes, respectively. Conclusion: Of the two biologic hallmarks of cancer evaluated in this study, a reduction in tumor glucose metabolism was more accurate than a reduction in tumor BF for predicting pCR in the different subtypes of breast cancer.