Phase I/II study testing the combination of AGuIX nanoparticles with radiochemotherapy and concomitant temozolomide in patients with newly diagnosed glioblastoma (NANO-GBM trial protocol).

BACKGROUND: Despite standard treatments including chemoradiotherapy with temozolomide (TMZ) (STUPP protocol), the prognosis of glioblastoma patients remains poor. AGuIX nanoparticles have a high radiosensitizing potential, a selective and long-lasting accumulation in tumors and a rapid renal elimination. Their therapeutic effect has been proven in vivo on several tumor models, including glioblastoma with a potential synergetic effect when combined with TMZ based chemoradiotherapy, and they are currently evaluated in 4 ongoing Phase Ib and II clinical trials in 4 indications (brain metastases, lung, pancreatic and cervix cancers) (> 100 patients received AGuIX). Thus, they could offer new perspectives for patients with newly diagnosed glioblastoma. The aim of this study is to determine the recommended dose of AGuIX as a radiosensitizer in combination with radiotherapy and TMZ during the concurrent radio-chemotherapy period for phase II (RP2D) and to estimate the efficacy of the combination. METHODS: NANO-GBM is a multicenter, phase I/II, randomized, open-label, non-comparative, therapeutic trial. According to a dose escalation scheme driven by a TITE-CRM design, 3 dose levels of AGuIX (50, 75 and 100 mg/kg) will be tested in phase I added to standard concomitant radio-chemotherapy. Patients with grade IV glioblastoma, not operated or partially operated, with a KPS ≥ 70% will be eligible for the study. The primary endpoints are i) for phase I, the RP2D of AGuIX, with DLT defined as any grade 3-4 NCI-CTCAE toxicity and ii) for phase II, the 6-month progression-free survival rate. The pharmacokinetics, distribution of nanoparticles, tolerance of the combination, neurological status, overall survival (median, 6-month and 12-month rates), response to treatment, and progression-free survival (median and 12-month rates) will be assessed as secondary objectives. Maximum sixty-six patients are expected to be recruited in the study from 6 sites. DISCUSSION: The use of AGuIX nanoparticles could allow to overpass the radioresistance to the reference treatment of newly diagnosed glioblastomas that have the poorest prognosis (incomplete resection or biopsy only). TRIAL REGISTRATION: Clinicaltrials.gov: NCT04881032 , registered on April 30, 2021. Identifier with the French National Agency for the Safety of Medicines and Health Products (ANSM): N°Eudra CT 2020-004552-15. PROTOCOL: version 3, 23 May 2022.

Phase I study of [131I] ICF01012, a targeted radionuclide therapy, in metastatic melanoma: MELRIV-1 protocol.

BACKGROUND: Benzamide-based radioligands targeting melanin were first developed for imaging melanoma and then for therapeutic purpose with targeted radionuclide therapy (TRT). [131I]ICF01012 presents a highly favorable pharmacokinetics profile in vivo for therapy. Tumour growth reduction and increase survival have been established in preclinical models of melanoma. According the these preclinical results, we initiate a first-in-human study aimed to determine the recommended dose of [131I]ICF01012 to administer for the treatment of patients with pigmented metastatic melanoma. METHODS: The MELRIV-1 trial is an open-label, multicentric, dose-escalation phase I trial. The study is divided in 2 steps, a selection part with an IV injection of low activity of [131I]ICF01012 (185 MBq at D0) to select patients who might benefit from [131I]ICF01012 TRT in therapeutic part, i.e. patient presenting at least one tumour lesion with [131I]ICF01012 uptake and an acceptable personalized dosimetry to critical organs (liver, kidney, lung and retina). According to dose escalation scheme driven by a Continual Reassessment Method (CRM) design, a single therapeutic injection of 800 MBq/m2, or 1600 MBq/m2, or 2700 MBq/m2 or 4000 MBq/m2 of [131I]ICF01012 will be administered at D11 (± 4 days). The primary endpoint is the recommended therapeutic dose of [131I]ICF01012, with DLT defined as any grade 3-4 NCI-CT toxicity during the 6 weeks following therapeutic dose. Safety, pharmacokinetic, biodistribution (using planar whole body and SPECT-CT acquisitions), sensitivity / specificity of [131I]ICF01012, and therapeutic efficacy will be assessed as secondary objectives. Patients who received therapeutic injection will be followed until 3 months after TRT. Since 6 to 18 patients are needed for the therapeutic part, up to 36 patients will be enrolled in the selection part. DISCUSSION: This study is a first-in-human trial evaluating the [131I]ICF01012 TRT in metastatic malignant melanomas with a diagnostic dose of the [131I]ICF01012 to select the patients who may benefit from a therapeutic dose of [131I]ICF01012, with at least one tumor lesion with [131I]ICF01012 uptake and an acceptable AD to healthy organ. TRIAL REGISTRATION: Clinicaltrials.gov : NCT03784625 . Registered on December 24, 2018. Identifier in French National Agency for the Safety of Medicines and Health Products (ANSM): N°EudraCT 2016-002444-17.

Laparoscopic management of advanced epithelial ovarian cancer after neoadjuvant chemotherapy: a phase II prospective multicenter non-randomized trial (the CILOVE study).

OBJECTIVE: The aim of this study was to explore the feasibility and safety of the laparoscopic approach after neoadjuvant chemotherapy among selected chemosensitive patients with advanced ovarian cancer. METHODS: The CILOVE study was a phase II prospective non-randomized multicenter study. It aimed to enroll 47 women with unresectable disease at the time of initial diagnosis (International Federation of Gynecology and Obstetrics (FIGO) stage IV and/or diffuse extensive carcinomatosis for advanced FIGO stage IIIC or patients unfit to withstand radical primary surgery), in response to chemotherapy and fit to undergo laparoscopy. RESULTS: Among the 48 patients enrolled in the trial, 44 (92%) patients underwent exploratory staging laparoscopy and, as a result, 41 patients were eligible for cytoreductive surgery. Among them, 32 were intended to be managed by laparoscopy and nine patients were managed by laparotomy. The conversion rate to laparotomy was 9.4% (3/32) and the reasons were multiple surgical adhesions (n=1), miliary carcinomatosis and adhesion to the intraperitoneal mesh (n=1), and poor laparoscopic evaluation of transverse colon involvement (n=1). All except one patient had optimal cytoreduction (97% complete cytoreduction, 3% incomplete cytoreduction (residual tumor <2.5 mm)). The median operative time was 267 min (range 146-415) and the median estimated blood loss was 150 mL (range 0-500). Two patients had intra-operative complications: one diaphragm rupture that was repaired during laparoscopy and one bradycardia. Six patients experienced early post-operative complications (<1 month), but there were no grade 3 and 4 complications (3 infections, 1 lymphoedema, 2 hemorrhage). After cytoreductive laparoscopy, the percentage of patients without progression at 12 months was 87.5%. CONCLUSIONS: Interval ovarian cytoreduction by a laparoscopic approach is safe and feasible for patients with a favorable response to chemotherapy. With the widespread use of neoadjuvant chemotherapy in the management of advanced ovarian cancer, a minimally invasive approach may be a potential option.

A multicenter prospective phase II study of postoperative hypofractionated stereotactic body radiotherapy (SBRT) in the treatment of early-stage oropharyngeal and oral cavity cancers with high risk margins: the STEREO POSTOP GORTEC 2017-03 trial.

BACKGROUND: Primary surgery is usually the mainstay treatment in early-stage oropharyngeal and oral cavity cancer. Typically, neck surgery is performed. Negative tumor margins are recommended (> 5 mm). If feasible, re-resection of any positive margin is preferred. Otherwise, postoperative radiotherapy is required. Adjuvant postoperative radiotherapy can be limited to the primary site for patients with pT1-T2 tumors and negative neck exploration. Currently, both fractionated external beam radiotherapy and brachytherapy can have a role in the postoperative management of early-stage oropharyngeal and oral cavity cancer with high risk margins. Another possible alternative could be postoperative stereotactic body radiotherapy (SBRT). The aim of this study is to evaluate postoperative SBRT in the treatment of early-stage oropharyngeal and oral cavity cancer with high risk margins. METHODS: The STEREO POSTOP study is a national, open-label, non-randomized phase II trial within the GORTEC network. Patients with early-stage oropharyngeal and oral cavity cancers with high risk margins indicating the need for postoperative radiation are eligible for enrollment. SBRT consists of a total dose of 36 Gy in 6 fractions over 2 weeks. The primary endpoint is severe late toxicity defined as 2-year toxicity of grade ≥ 3 according to CTCAE V4.03 classification. The secondary endpoints include acute toxicity (≤ 3 months), local and locoregional control, disease-free and overall survival, quality of life of patients, nutritional impact and predictive factors of toxicity. The experimental design chosen is a one-step Fleming plan design without interim analysis as the primary endpoint will be evaluated at a 2-year follow-up. Ninety patients will be recruited. The study was started in January 2018 with a 4-year enrollment period and an estimated completion in January 2024. DISCUSSION: This study is the first prospective trial to evaluate head and neck cancer postoperative SBRT in the setting of early-stage oropharyngeal and oral cavity cancers with high risk margins. SBRT is an attractive option because it delivers a highly conformal dose of radiation in a limited number of fractions (like brachytherapy but with less contraindication), with steep dose gradients resulting in reduced normal tissue irradiation and with a short overall treatment time. TRIAL REGISTRATION: Clinicaltrials.gov : NCT03401840 , registered on 17-1-2018. Identifier in French National Agency for the Safety of Medicines and Health Products (ANSM): N°ID - RCB 2017-A02058-45, registered on July 2017. Protocol version: Version 3 dated from 25th November 2019.

A decrease in brown adipose tissue activity is associated with weight gain during chemotherapy in early breast cancer patients.

BACKGROUND: A decrease in thermogenesis is suspected to be implicated in the energy expenditure reduction during breast cancer treatment. This study aimed to investigate the impact of chemotherapy on the metabolic activity of brown adipose tissue (BAT) and the link with weight variation. METHODS: This was an ancillary analysis of a multicentre trial involving 109 HER2+ breast cancer patients treated with neoadjuvant chemotherapy. A centralised review of 18F-FDG uptake intensity (SUVmax) in specific BAT regions (cervical and supraclavicular) was conducted on two PET-CT scans for each patient (before and after the first course of chemotherapy). RESULTS: Overall, after one course of chemotherapy a significant decrease of 4.4% in 18F-FDG-uptake intensity was observed. It was not correlated to initial BMI, age or season. During chemotherapy, 10.1% (n = 11) of the patients lost weight (- 7.7 kg ± 3.8 kg; ie, - 9.4% ± 3.7%) and 29.4% (n = 32) gained weight (+ 5.1 kg ± 1.7 kg; ie, + 8.5% ± 2.6%). Among these subgroups, only the patients who had gained weight underwent a significant decrease (13.42%) in 18F-FDG uptake intensity (p = 0.042). CONCLUSION: This study is the first to highlight in a large cohort of patients the negative impact of chemotherapy on brown adipose tissue activity. Weight gain during chemotherapy could thus potentially be explained in part by a decrease in brown adipose tissue activity.

Improvement in adherence to Capecitabine and Lapatinib by way of a therapeutic education program.

PURPOSE: A patient non-adherence with oral anticancer agents is a well-recognized barrier to effective treatment. The aim of this prospective study was to evaluate the efficacy of a therapeutic education program among non-adherent patients treated with Capecitabine alone or associated with Lapatinib. METHODS: Sixty-five cancer patients were enrolled. Among them, 55 participated in the first observational phase of the study, measuring adherence using electronic MEMS pillboxes (medication event monitoring system). An adherence score was assessed in the form of a composite adherence score including intake dose and intake intervals. Ten non-adherent patients (adherence score < 80%) were included in the intervention phase of the study and were enrolled on a therapeutic education program. The efficacy of the program was evaluated on the basis of an improvement in adherence scores. We also studied factors influencing adherence. RESULTS: The average adherence score was 83.6 ± 15.7% in the overall population. Forty-one patients were adherent (adherence score > 80%) and 14 patients were non-adherent (adherence score < 80%). The therapeutic education program for non-adherent patients (n = 10) increased their adherence score by 17.8% and led 60% of these patients to become adherent. The number of toxicities during the first cycles was a predictive factor for non-adherence. CONCLUSION: This study showed an improvement in adherence to Capecitabine ± Lapatinib among non-adherent patients by way of a therapeutic education program.

Quality of life for older patients with cancer: a review of the evidence supporting melatonin use.

PURPOSE: The proportion of older populations living with cancer is on the increase. Maintaining or improving their quality of life (QoL) has become an important goal in the treatment of cancer and has become an endpoint in clinical trials. Melatonin regulates a wide variety of physiological functions and is involved in the initiation of sleep and the improvement of QoL. With age, the secretion of melatonin decreases and could lead to a deterioration in QoL. METHODS: Literature searches were conducted using the PubMed database. The search terms and derivatives of "metastatic cancer", "older patients", "quality of life" and "melatonin" were used. Titles and abstracts were screened to identify whether studies were relevant for full-text screening. RESULTS: There is major concern about the symptoms older cancer patients encounter during treatment because they can impact their QoL. Melatonin supplementation presents several benefits for older patients: improvement in survival, decrease in symptoms induced by cancer and cancer treatment, and also improvements in quality of life. CONCLUSION: It therefore seems appropriate to study the impact of melatonin supplementation during cytotoxic therapy on QoL among elderly patients with metastatic cancer. The use of melatonin as a therapeutic strategy seems particularly suitable for elderly patients, a population known to secrete significantly less melatonin. However, to date, no studies have been conducted in this population.

Treatment-Induced Cardiotoxicity in Breast Cancer: A Review of the Interest of Practicing a Physical Activity.

Physical activity is known to prevent the occurrence of cancer and decrease the risk of breast cancer. At diagnosis of breast cancer, fewer than half of the patients reach the international recommendation for physical activity. However, breast cancer patients, and particularly HER2+ breast cancer patients, are exposed to treatment-induced cardiotoxicity because of a side effect of 2 molecules used in standard therapy to treat these tumors, i.e., anthracycline and trastuzumab. Cardiotoxicity can sometimes lead to discontinuation of the treatment and even to the development of cardiovascular diseases. Exercise is known to protect the cardiovascular system in the healthy population. Consequently, being physically active during treatment appears to be a way to prevent the negative impact of cancer treatment on the heart in this population. In particular, aerobic exercising could have a protective effect against treatment-induced cardiotoxicity. A supervised physical activity program seems to be the best way for breast cancer patients to be active during treatment. However, there is very little information, and in particular a lack of guidelines, on exercising available to patients. The interventional trials that have been conducted on this topic are very heterogeneous and no standard recommendations have been made available for cancer patients thus far. An effective physical activity program needs to take each patient's barriers and motivations into account in order to encourage the practice of physical activity throughout treatment. To ensure the success of the program, it is essential to facilitate adherence and especially maintain motivation. Further studies are needed to determine what practice guidelines oncologists should give their patients.

Prospective Study on Body Composition, Energy Balance and Biological Factors Changes in Post-menopausal Women with Breast Cancer Receiving Adjuvant Chemotherapy Including Taxanes.

In breast cancer patients, weight and fat mass changes observed after chemotherapy have been related to poor prognosis but some recent works using modern chemotherapy failed to find this correlation with weight gain. In this study, the extent of changes in weight and body composition (DEXA, impedance) was characterized until six months after current chemotherapy, in 50 post-menopausal women with breast cancer. The evolution of factors contributing to the energy balance and some biological factors were also described. During chemotherapy, 20% of women lost weight due to both fat (-13.1% ± 10.3) and lean soft tissue mass loss (-3.6% ± 4.6). Twenty percent of women gained weight. No significant fat mass gain was observed in these women but significant water gain was highlighted. Six months later, women who gained weight presented a gain in fat mass (15.4% ± 19.0), especially in the abdominal region. Age and initial BMI were negatively correlated with fat mass in multivariate analyzes (r = 0.486, P = 0.0030). No significant variation of the glucose homeostasis, triglycerides, and HDL-Cholesterol was found six months after chemotherapy. These results do not suggest major adverse metabolic disturbances six months after modern chemotherapy and only a mild fat mass gain was observed in women who gained weight.

The New Combination Docetaxel, Prednisone and Curcumin in Patients with Castration-Resistant Prostate Cancer: A Pilot Phase II Study.

OBJECTIVES: Favorable phase I results justified this pilot phase II study to assess the efficacy of docetaxel/curcumin in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (CRPC). METHODS: Thirty patients with progressing CRPC and a rising prostate-specific antigen (PSA) received docetaxel/prednisone in standard conditions for 6 cycles in combination with per os curcumin, 6,000 mg/day (day -4 to day +2 of docetaxel). The co-primary endpoint was the overall response rate determined by PSA and target assessments. An ancillary study assessed the seric values of chromogranin A (CgA) and neuron-specific enolase (NSE). RESULTS: Twenty-six patients received the scheduled treatment, 2 progressed and 2 died before the end of treatment. A PSA response was observed in 59% of patients (14% of PSA normalization) and achieved within the first three cycles for 88% of responders. Partial response was reached for 40% of evaluable patients. The regimen was well tolerated, and no adverse event was attributed to curcumin. Twenty patients were 100% curcumin compliant. The PSA level and objective response rate were not correlated with the serum values of CgA and NSE. CONCLUSION: This study produced additional data on curcumin as a treatment for cancer, with a high response rate, good tolerability and patient acceptability, justifying the interest to conduct a randomized trial.

Neurotoxicity as a prognostic factor in patients with metastatic breast cancer treated with ixabepilone as a first-line therapy.

OBJECTIVE: This study is a longitudinal follow-up of metastatic breast cancer patients treated with ixabepilone as first-line chemotherapy, with the aim to evaluate the association between a mechanism-based neurotoxicity and the efficacy of ixabepilone. PATIENTS AND METHODS: At the 2 main investigational sites of a phase II clinical trial, 50 patients previously treated with anthracycline received ixabepilone. A chart review was performed to evaluate overall survival (OS) and time to progression (TTP) and to describe the subsequent treatments. RESULTS: The severe neurotoxicity induced by ixabepilone (38%) is correlated with a higher overall response rate to ixabepilone (79 vs. 48%; p = 0.042), a longer TTP (11.4 vs. 6.8 months; p = 0.023) and a longer OS (36.6 vs. 19.9 months; p = 0.05). After ixabepilone discontinuation, patients received a median of 4 subsequent chemotherapy lines (range 1-12). Among the 31 patients who received taxanes, neither the neurotoxicity incidence under treatment with taxanes nor the response was affected by a previous occurrence under ixabepilone treatment. CONCLUSION: These findings suggest that neurotoxicity development under ixabepilone treatment is a predictor of treatment outcomes as well as a favorable prognostic factor. It highlights the risk-to-benefit ratio issue of ixabepilone. We noticed the possibility to treat patients with taxanes after ixabepilone without systematic recurrent neurotoxicity.

Brown adipose tissue activity in relation to weight gain during chemotherapy in breast cancer patients: a pilot study.

Weight gain has been reported in early stage breast cancer patients during chemotherapy, but the involved mechanisms remain unclear. A chemotherapy-induced decrease of brown adipose tissue (BAT) activity may partly contribute to weight gain in these patients. A positron emission tomography/computed tomography scan was performed at baseline and after 1 course of docetaxel + trastuzumab treatment in 26 breast cancer women. Variation of the maximal standardized uptake value of BAT in the cervical and supraclavicular regions between the 2 measures was assessed according to weight changes. Overall, (18)F-FDG uptakes in BAT decreased by 11.3% after 1 course of chemotherapy (p = 0.03). No correlation was found between the baseline values of (18)F-FDG uptake and body mass index or age of patients, but as expected (18)F-FDG uptake was dependent on season period. Among the patients, 35% gained weight, 25% lost weight, and 40% remained stable. Women who gained weight during chemotherapy experienced a significant decrease of (18)F-FDG uptake in BAT (p = 0.005). Decreased activity of BAT was associated with body weight gain during chemotherapy. These original data suggest for the first time that BAT modulation by chemotherapy would be a potential contributor to body weight gain through blunted thermogenesis in breast cancer patients.

Non-invasive intracranial pressure monitoring for high-grade gliomas patients treated with radiotherapy: results of the GMaPIC trial.

Introduction: Patients with high-grade gliomas are at risk of developing increased intracranial hypertension (ICHT) in relation to the increase in volume of their tumor. ICP change cannot be measured by invasive method but can be estimated by using routine clinical signs, in combination with a standard imaging method, magnetic resonance imaging (MRI). A non-invasive monitoring of ICP could be of interest in high-grade glioma, in particular after radiotherapy treatment with as major side effect a cerebral oedema. Patients and Methods: This prospective clinical study aimed to compare the ICP changes (estimated by a non-invasive method based upon distortion product otoacoustic emissions (DPOAE) monitoring) with volume changes observed on MRI in patients with high-grade gliomas treated with radiotherapy. DPOAE measurements were performed one month after the end of radiotherapy and then every 3 months for one year. At each visit, the patient also underwent MRI as well as an evaluation of clinical signs. Results: The variation in the estimate of intracranial pressure readout measured at each follow-up visit (in absolute value with respect to the baseline measurements) was significantly associated with the variation of T2/FLAIR volume (n=125; p<0.001) with a cut off value of change ICP readout of 40.2 degrees (e.i. an estimated change of 16 mm Hg). Discussion: The GMaPIC trial confirm the hypothesis that the ICP change estimated by DPOAEs measurement using a non-invasive medical device is correlated with the change of the tumor or edema in high grade glioma after radiotherapy. The device could thus become an easy-to-use and non-invasive intracranial pressure monitoring tool for these patients. Clinical Trial Registration: Clinicaltrials.gov, identifier (NCT02520492).

A phase-II study based on dose adjustment according to UGT1A1 polymorphism: is irinotecan underdosed in first-line FOLFIRI regimen for mCRC?

PURPOSE: Irinotecan has considerable importance in the treatment of metastatic colorectal cancer (mCRC). UDP-glucoronyltransferase (UGT) 1A1 is responsible for the inactivation of SN-38, a metabolite of irinotecan. Depending on UGT1A1 polymorphism, the activity of the UGT enzyme can be reduced leading to more frequent occurrence of adverse events related to irinotecan. The present study aimed to assess the safety and efficacy of different doses of irinotecan adjusted according to UGT1A1 polymorphism. METHODS: Thirty-four patients treated with FOLFIRI as first-line treatment for mCRC were included in this study. The irinotecan dosage was adapted on the basis of UGT1A1 polymorphisms: *1/*1 (370 mg/m2); *1/*28 (310 mg/m2), and *28/*28 (180 mg/m2). The incidence of grades 3 and 4 toxicities (neutropenia, febrile neutropenia, and diarrhoea) was recorded. Response was assessed according to the RECIST 1.1 criteria. RESULTS: On the basis of UGT1A1 genotyping, 20 patients were *1/*1 (58.8%), 12 were *1/*28 (35.3%) and 2 were *28/*28 (5.9%). Seven patients experienced at least one severe toxicity, i.e., 21% of the population, amounting to eleven adverse events. Concerning the response rate, 15 patients (44%) had partial or complete response. CONCLUSION: This study demonstrates that mCRC patients treated with FOLFIRI can tolerate a higher dose of irinotecan than the standard dose, i.e., > 180 mg/m2, on the basis of their UGT1A1 genotype, without increased toxicities. TRIAL REGISTRATION: NCT01963182 (registered on 16/10/2013, Clermont-Ferrand, France).

Postoperative SBRT in the treatment of early-stage oropharyngeal and oral cavity cancers with high-risk margins: A dosimetric comparison of volumetric modulated arc therapy with or without non-coplanar arcs and acute toxicity outcomes from the STEREOPOSTOP GORTEC 2017-03 phase 2 trial.

Background and purpose: The STEREO POSTOP GORTEC 2017-03 phase 2 trial (NCT03401840) evaluates postoperative stereotactic body radiotherapy (SBRT) in case of high-risk margins for pT1-T2/N0 oropharyngeal and oral cavity tumors. The present ancillary study aimed to compare the dosimetric impact of adding non-coplanar arcs to the volumetric modulated arc therapy (VMAT) technique and to evaluate acute toxicities on the first patients included in this trial. Materials and methods: Ten patients were included. Patients were treated with Novalis TX®. The total dose was 36 Gy (100 % isodose line) in 6 fractions, treated every other day. Two treatment plans were created for each patient: one plan using 2 coplanar arcs only (VMATc) and one plan using coplanar and 3 non-coplanar arcs (VMATc + nc). Acute toxicity was evaluated according to NCI CTCAE criteria V4.03. Results: Median age was 62 years. Localization of tumor was the mobile tongue for 6 patients, floor of mouth for 2, cheek for 1, and gingiva for 1. Six patients had pT2N0 tumors (AJCC 7th edition) and 4 had pT1N0. Mean CTV and PTV volumes were 36.4 and 56.1 cc respectively. Mean PTV coverage by the 36 Gy isodose was 98.2 % for both techniques (p = ns), with comparable conformity indexes (1.1 for VMATc vs 1.07 for VMATc + nc; p = 0.23). VMATc + nc had a significantly better gradient index (3.45 vs 2.97; p = 0.01), resulting in a significantly better sparing of most organs at risk. For example, mean Dmean to the oral cavity, lips, and homolateral parotid were respectively of 16.8 Gy, 11.1 Gy, and 10.4 Gy for VMATc vs 14.8 Gy (p = 0.005), 8.1 Gy (p = 0.001), 6.5 Gy (p = 0.04) for VMATc + nc. No grade ≥ 4 or higher acute toxicity was reported. The most common acute toxicity was grade ≥ 2 mucositis. Conclusion: VMATc + nc had better dosimetric outcomes than VMATc and has become the standard technique for patients treated in the STEREO POSTOP GORTEC 2017-03 trial (NCT03401840) in our institution. Acute toxicity appears acceptable.

Immune status is more affected by age than by carotenoid depletion-repletion in healthy human subjects.

Prospective studies have indicated an age-related impairment of the immune response. Carotenoids have been hypothesised to enhance immune cell function. The aim of the present study was to describe the age-related effects and the impact of in vivo dietary carotenoid depletion and repletion on specific and non-specific immunity. A total of ninety-eight healthy male subjects (aged 20-75 years) received a carotenoid-depleted diet for 3 weeks and were then supplemented daily for 5 weeks with 30 mg ß-carotene, 15 mg lycopene and 9 mg lutein. Blood samples were collected at study entry, after depletion and supplementation, and biomarkers of immune status were determined. We found that serum IgA levels were positively correlated with ageing. Lymphocyte phenotyping indicated an increase with age in the memory T-helper cell subpopulation (CD4⁺CD45RO⁺) concomitantly with a decrease in naive T-helper cells (CD4⁺CD45RA⁺). A significant increase in the natural killer cells subpopulation and a small decrease in B lymphocytes were also observed, especially for the oldest volunteers. From ex vivo cell function exploration, a positive correlation was observed between age and IL-2 production of phytohaemagglutinin-stimulated lymphocytes. Neutrophils' bactericidal activity was significantly impaired with age (from 50 years) and was modulated by carotenoid status. An age effect was found on neutrophils' spontaneous migration but not on directed migration. Immune response in healthy human subjects is mostly affected by age rather than by dietary carotenoid depletion and repletion. Even in carefully selected healthy volunteers, some age-related immune changes occur predominantly from 50 years onwards. This immunosenescence could generate a loss in the immune system adjustment capacity.

Assessment of 99mTc-NTP 15-5 uptake on cartilage, a new proteoglycan tracer: Study protocol for a phase I trial (CARSPECT).

Background: 99mTc-NTP 15-5 is a SPECT radiotracer targeting proteoglycans (PG), components of the cartilaginous extracellular matrix. Imaging of PGs would be useful for the early detection of cartilage disorders (osteoarthritis, arthritis and chondrosarcoma, Aromatase Inhibitor associated arthralgia (AIA) in breast cancer), and the follow-up of patients under treatment. According to preclinical study results, 99mTc-NTP 15-5, is a good candidate for a specific functional molecular imaging of joints. We intend to initiate a first in-human study to confirm and quantify 99mTc-NTP 15-5 uptake in healthy joints. Methods: As the clinical development of this radiotracer would be oriented toward the functional imaging of joint pathologies, we have chosen to include patients with healthy joints (unilateral osteoarthritis of the knee or breast cancer with indication of AI treatment). This phase I study will be an open-label, multicenter, dose-escalation trial of a radiopharmaceutical orientation to determine the recommended level of activity of 99mTc-NTP 15-5 to obtain the best joint tracer contrasts on images, without dose limiting toxicity (DLT). The secondary objectives will include the study of the pharmacology, biodistribution (using planar whole body and SPECT-CT acquisitions), toxicity, and dosimetry of this radiotracer. The dose escalation with 3 activity levels (5, 10, and 15 MBq/kg), will be conditioned by the absence at the previous level of DLT and of a visualized tracer accumulation on more than 80% of healthy joints as observed on scintigraphy performed at ≤ 2 h post-injection. Discussion: This first in-human phase I trial will be proof-of-concept of the relevance of 99mTc-NTP 15-5 as a cartilage tracer, with the determination of the optimal methodology (dose and acquisition time) to obtain the best contrast to provide a functional image of joints with SPECT-CT. Trial registration number: Clinicaltrials.gov: NCT04481230. Identifier in French National Agency for the Safety of Medicines and Health Products (ANSM): N°EudraCT 2020-000495-37.

Adapted Physical Activity for Breast Cancer Patients Treated with Neoadjuvant Chemotherapy and Trastuzumab Against HER2 (APACAN2): A Protocol for a Feasibility Study.

BACKGROUND: The standard care for HER2-positive breast cancer is chemotherapy plus a HER2-directed therapy. This can lead to treatment-induced cardiotoxicity. On the other hand, the practice of physical activity is known to improve cardiac function; thus HER2-positive breast cancer patients could draw particular benefit from physical activity during treatment. However, at the time of diagnosis for breast cancer, the majority of patients are insufficiently active according to physical activity recommendations of World Health Organisation, and it is difficult to remain or become active during the treatment. There is a lack of data in the literature on the optimal program to propose to patients to encourage them to be active during treatment. The aim of our study is to assess the feasibility of a home-based physical activity program during neoadjuvant chemotherapy and trastuzumab for HER2-positive breast cancer. METHODS: The APACAN2 study is a single-centre, non-randomized interventional trial. Patients with HER2-positive breast cancer treated with anthracycline-based neoadjuvant chemotherapy and trastuzumab are eligible for enrolment. The supervised home-based physical activity program takes place during neoadjuvant chemotherapy (NACT). It combines aerobic and strengthening exercises. The primary endpoint is the proportion of patients reaching the international physical activity recommendations, i.e. 150 minutes of moderate-intensity activity per week at the end of NACT. The study started in April 2018 and seventy patients are expected to be recruited. DISCUSSION: In the literature, the majority of studies on practice of physical activity in breast cancer focus on adjuvant chemotherapy or on the period after the end of treatment. To the best of our knowledge, the APACAN2 study is the first to evaluate a home-based physical activity program during neoadjuvant chemotherapy for HER2-positive breast cancer. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov: NCT02963363, registered on July 11, 2016. Identifier with the French National Agency for the Safety of Medicines and Health Products N°ID RCB 2016-A01344-47, registered in August 2016. Protocol: version 8, 24 February 2021.

Risk Factors Associated With Complications After Unilateral Immediate Breast Reconstruction: A French Prospective Multicenter Study.

BACKGROUND/AIM: For women who have undergone a mastectomy, breast reconstruction provides psychological as well as aesthetic benefits. Thus, many patients ask for an immediate breast reconstruction (IBR). The present study focuses on risk factors assiociated with complications after IBR. PATIENTS AND METHODS: A national prospective study (2007-2009) was conducted on 404 patients who underwent an unilateral IBR: 205 implants alone (IA) including 46 tissue expanders, 91 latissimus dorsi musculocutaneous flaps with implant (LDI), 78 autologous latissimus dorsi musculocutaneous flaps (LD), and 30 autologous transverse rectus abdominis musculocutaneous flaps (TRAM). Outcomes concerned major and minor complications, as well as early and late complications. RESULTS: Related risks of complications were different according to the IBR technique. Major complications rate remained moderate and concerned 15% of patients. Obesity and diabetes significantly increased the incidence of major complications. CONCLUSION: To reduce complication rate, the risk factors associated with each type of IBR should be taken into account.

Multicenter randomized phase II study comparing docetaxel plus curcumin versus docetaxel plus placebo in first-line treatment of metastatic castration-resistant prostate cancer.

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) patients have a poor prognosis, and curcumin is known to have antineoplastic properties. On the basis of previous phase I and phase II studies, we investigated whether the association of curcumin with docetaxel could improve prognosis among mCRPC patients. METHODS: A total of 50 mCRPC patients (included from June 2014 to July 2016) treated with docetaxel in association with oral curcumin (6 g/d for 7 days every 3 weeks) versus placebo were included in this double-blind, randomized, phase II study. The primary endpoint was to evaluate the time to progression. Among the secondary endpoints, compliance, overall survival, prostate-specific antigen (PSA) response, safety, curcumin absorption, and quality of life were investigated. An interim analysis was planned in the modified intention-to-treat population with data at 6 months (22 patients per arm). RESULTS: Despite good compliance and a verified absorption of curcumin, no difference was shown for our primary endpoint: progression-free survival (PFS) between the placebo and curcumin groups was, respectively, 5.3 months versus 3.7 months, p = 0.75. Similarly, no difference was observed for the secondary objectives: PSA response rate (p = 0.88), overall survival (p = 0.50), and quality of life (p = 0.49 and p = 0.47). CONCLUSION: Even though our previous studies and data in the literature seemed to support an association between curcumin and cancer therapies in order to improve patient outcome and prognosis, the results from this interim analysis clearly showed that adding curcumin to mCRPC patients' treatment strategies was not efficacious. The study was discontinued on the grounds of futility.