Helical TomoTherapy® allows precise and homogeneous tumour coverage and excellent sparing of organs at risk. We present here our treatment technique, dosimetric results, and our first clinical data ...for patients receiving total body irradiation as part of the conditioning regimen before hematopoietic stem cell transplantation.
The cohort consisted of 11 patients who were treated in our institution between August 2014 and January 2016. The total dose was 12Gy in six fractions in three days. We collected the dose distribution information in the treatment volumes, organs at risk and area of junction. We report retrospectively the clinical events during the first 6 months after the procedure.
Median age was 31 years (range, 18–57 years). Median D98% was 11.5Gy (range: 6.6–11.9Gy). The median of the mean doses to the lungs was 8.7Gy (range: 8.5–9.3Gy). The mean dose for the junction area was 12Gy (range: 11.9–12.1Gy). All patients had the total procedure, and all underwent successful engraftment. During the first six months, nine patients had at least one grade 3 or 4 toxicity that was due essentially to graft versus host disease. No patient had radiation pneumonitis. The toxicities were both more frequent and of higher grade during the first three months.
Total body irradiation using helical TomoTherapy® is feasible. It allows a very good homogeneity of dose and conformity with an acceptable tolerance. It could deliver higher doses to sites at high risk of recurrence (bone marrow, sanctuary sites), while sparing major normal organs like lungs, liver, and kidneys. This reduction of dose could lead to reduced severity and frequency of late complications.
La tomothérapie hélicoïdale permet une couverture de dose précise et homogène au niveau de la cible tout en évitant efficacement les organes à risques. Nous présentons dans cet article notre technique de traitement, nos résultats dosimétriques, et les données cliniques précoces chez des patients ayant reçu une irradiation corporelle totale dans leur conditionnement avant greffe de cellules souches hématopoïétiques.
La cohorte a inclus 11 patients qui ont été pris en charge dans notre institution entre août 2014 et janvier 2016. La dose totale était de 12Gy en six fractions sur troisjours. Nous avons collecté les données de distribution de dose dans les volumes cibles, les organes à risque et au niveau de la zone de jonction. Nous rapportons rétrospectivement la toxicité clinique survenue dans les six mois suivant la procédure.
L’âge médian était de 31 ans (18 à 57 ans). La médiane du D98 % était de 11,5Gy (6,6–11,9Gy). La médiane de la dose moyenne aux poumons était de 8,7Gy (8,5–9,3Gy). La dose moyenne au niveau de la zone de jonction était de 12Gy (11,9–12,1Gy). Tous les patients ont pu compléter l’ensemble de la procédure, et ont pu recevoir la greffe de cellules souches prévue. Dans les six premiers mois, neuf patients ont souffert d’au moins une toxicité de grade 3 ou 4, qui était due essentiellement à la réaction de greffon contre l’hôte (GVH). Aucun patient n’a été atteint de pneumopathie radique. La toxicité était à la fois plus fréquente et de grade plus élevé dans les trois premiers mois.
L’utilisation de la tomothérapie hélicoïdale pour l’irradiation corporelle totale est réalisable. Cela permet une très bonne homogénéité de dose et une très bonne conformation à la cible, avec une tolérance acceptable. Cette technique pourrait permettre de délivrer des doses plus élevées aux sites à haut risque de rechute (moelle osseuse, sites sanctuaires), tout en évitant les organes à risque importants, comme les poumons, le foie et les reins. Cette réduction de dose pourrait permettre de réduire la sévérité et la fréquence des complications tardives.
To determine the indications for radiotherapy in salivary gland cancer and to specify the modalities and target radiation volumes.
The French Network of Rare Head and Neck Tumors (REFCOR) formed a ...steering group which drafted a narrative review of the literature published on Medline and proposed recommendations. The level of adherence to the recommendations was then assessed by a rating group, according to the formal consensus method.
Postoperatively, radiotherapy to the primary tumor site±to the lymph nodes is indicated if one or more of the following adverse histoprognostic factors are present (risk>10% of locoregional recurrence): T3–T4 category, lymph node invasion, extraglandular invasion, close or positive surgical margins, high tumor grade, perineural invasion, vascular emboli, and/or bone invasion. Intensity-modulated radiation therapy (IMRT) is the gold standard. For unresectable cancers or inoperable patients, carbon ion hadrontherapy may be considered.
Radiotherapy in salivary gland cancer is indicated in postoperative situations in case of adverse histoprognostic factors and for inoperable tumors.
To determine the therapeutic indications for systemic medical treatment in the management of adenoid cystic carcinoma (ACC) according to the clinical situation.
The French Network of Rare Head and ...Neck Tumors (REFCOR) formed a steering group, which drafted a narrative review of the literature published on Medline and proposed recommendations. The level of adherence to the recommendations was then assessed by a rating group, according to the formal consensus method.
ACCs are rare tumors and there is currently insufficient evidence to indicate chemotherapy at the localized stage. At the metastatic stage, progression is often slow. In case of oligometastatic ACC, local treatment should be discussed. The most often indolent nature of polymetastatic ACC can allow management by active surveillance. Molecular screening is recommended, for abnormalities potentially accessible to targeted therapy.
ACCs are rare tumors for which there are currently few effective medical treatments. It is therefore recommended to include patients in clinical trials.
OBJECTIVETo determine the therapeutic indications for systemic medical treatment in the management of salivary gland carcinoma (excluding adenoid cystic carcinoma) according to the clinical ...situation.MATERIALS AND METHODSThe French Network of Rare Head and Neck Tumors (REFCOR) formed a steering group who drafted a narrative review of the literature published on Medline and proposed recommendations. The level of adherence to the recommendations was then assessed by a rating group, according to the formal consensus method.RESULTSSalivary gland carcinoma is rare and there is currently insufficient evidence to indicate chemotherapy at the localized stage. At the metastatic stage, initial management can be based on a phase of monitoring for indolent disease. Some histological subtypes (salivary duct carcinoma and adenocarcinoma) are more aggressive and require systemic treatment from the outset. To guide systemic treatment, it is recommended to perform immunohistochemistry and molecular biology analyses (overexpression of HER2 and androgen receptors, NTRK fusion, next-generation sequencing).CONCLUSIONSalivary gland carcinoma is a rare tumor for which there are currently few effective medical treatments. It is therefore recommended to include patients in clinical trials.
Abstract
Background
Nivolumab is a standard of care in patients (pts) with metastatic clear cell renal cell carcinoma (mccRCC) after failure of prior anti-angiogenic tyrosine-kinase inhibitors ...(TKIs). We evaluated the impact of corticosteroids (CS) during nivolumab in pts with mccRCC as part of a prospective clinical trial.
Methods
We conducted an ancillary study of the GETUG-AFU 26 NIVOREN study (NCT03013335), a multicenter prospective phase II safety study of nivolumab in mccRCC after progression on anti-angiogenic TKIs. Patients receiving CS at nivolumab initiation were excluded. Overall survival (OS) and progression free survival (PFS) of pts exposed to CS (≥ 10 mg of prednisone equivalents) or not during nivolumab were assessed. To overcome immortal time bias, we used two different landmark analysis methods. We first excluded pts who progressed or died before specified landmark timepoints (12 and 16 weeks). In a second method, patients treated with CS before landmark timepoints (12 and 16 and 24 weeks) were used to evaluate the effect of an early exposition to CS.
Results
Among the 665 evaluable pts, with a median follow up of 23.9 months, 113 (17 %) were exposed to CS during nivolumab, mainly to treat immune-related adverse events of any grade (74%). Other indications included infections (15%), complications of radiotherapy and chronic obstructive pulmonary disease. Median time to the first CS treatment was 21.6 weeks. Using a landmark at 12 weeks, OS rate at 12 months were 85.6% and 73.5% in pts exposed or not to CS hazard ratio (HR), 0.57; p = 0.0017. PFS rate at 12 months were 61.1% and 41.6% in pts exposed or not to CS (HR, 0.63; p = 0.0065). Landmark analyses at 16 weeks showed similar results. With the second landmark method, no differences in PFS or OS were observed between groups at 12 and 16 weeks. With a landmark set at 24 weeks, OS was similar in pts exposed or not to CS (HR, 1.14; p = 0.55).
Conclusions
The use of CS during nivolumab in mccRCC is not associated with a detrimental effect on survival outcomes. The positive association of corticosteroid use for irAEs with outcomes was not confirmed by second landmark modalities. Immortal time bias should be carefully considered when studying time-dependent variable.
Clinical trial identification
NCT03013335.
Legal entity responsible for the study
UNICANCER.
Funding
Bristol-Myers Squibb.
Disclosure
M. Gross-Goupil: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Ipsen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis. B. Laguerre: Honoraria (self), Travel / Accommodation / Expenses: BMS; Honoraria (self), Travel / Accommodation / Expenses: Pfizer; Honoraria (self): Novartis; Honoraria (self): Ipsen. P. Barthelemy: Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Janssen-Cilag; Honoraria (self), Advisory / Consultancy: Sanofi. S. Negrier: Honoraria (self): Pfizer; Honoraria (self): Bms; Honoraria (self): Novartis; Honoraria (self): IPSEN; Honoraria (self): Euspharma. L. Geoffrois: Honoraria (self), Travel / Accommodation / Expenses: MSD; Honoraria (self), Travel / Accommodation / Expenses: BMS; Honoraria (self): Ipsen; Honoraria (self): Novartis; Travel / Accommodation / Expenses: Merck. S. Ladoire: Advisory / Consultancy, Travel / Accommodation / Expenses: BMS. M. Laramas: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: SANOFI; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer; Speaker Bureau / Expert testimony: BMS; Speaker Bureau / Expert testimony: Amgen; Speaker Bureau / Expert testimony: IPSEN; Speaker Bureau / Expert testimony: Janssen; Travel / Accommodation / Expenses: Eisai. S. Oudard: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Ipsen. B. Escudier: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Roche; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Eusa; Advisory / Consultancy, Research grant / Funding (institution): Avevo; Advisory / Consultancy, Research grant / Funding (institution): Pfizer. L. Albiges: Advisory / Consultancy, Compensated to institution: Pfizer; Advisory / Consultancy, Compensated to institution: Novartis; Advisory / Consultancy, Compensated to institution: BMS; Advisory / Consultancy, Compensated to institution: Ipsen; Advisory / Consultancy, Compensated to institution: Roche; Advisory / Consultancy, Compensated to institution: MSD; Advisory / Consultancy, Compensated to institution: AstraZeneca. All other authors have declared no conflicts of interest.
Nivolumab is a standard of care in patients (pts) with metastatic clear cell renal cell carcinoma (mccRCC) after failure of prior anti-angiogenic tyrosine-kinase inhibitors (TKIs). We evaluated the ...impact of corticosteroids (CS) during nivolumab in pts with mccRCC as part of a prospective clinical trial.
We conducted an ancillary study of the GETUG-AFU 26 NIVOREN study (NCT03013335), a multicenter prospective phase II safety study of nivolumab in mccRCC after progression on anti-angiogenic TKIs. Patients receiving CS at nivolumab initiation were excluded. Overall survival (OS) and progression free survival (PFS) of pts exposed to CS (≥ 10mg of prednisone equivalents) or not during nivolumab were assessed. To overcome immortal time bias, we used two different landmark analysis methods. We first excluded pts who progressed or died before specified landmark timepoints (12 and 16 weeks). In a second method, patients treated with CS before landmark timepoints (12 and 16 and 24 weeks) were used to evaluate the effect of an early exposition to CS.
Among the 665 evaluable pts, with a median follow up of 23.9 months, 113 (17 %) were exposed to CS during nivolumab, mainly to treat immune-related adverse events of any grade (74%). Other indications included infections (15%), complications of radiotherapy and chronic obstructive pulmonary disease. Median time to the first CS treatment was 21.6 weeks. Using a landmark at 12 weeks, OS rate at 12 months were 85.6% and 73.5% in pts exposed or not to CS hazard ratio (HR), 0.57; p=0.0017. PFS rate at 12 months were 61.1% and 41.6% in pts exposed or not to CS (HR, 0.63; p=0.0065). Landmark analyses at 16 weeks showed similar results. With the second landmark method, no differences in PFS or OS were observed between groups at 12 and 16 weeks. With a landmark set at 24 weeks, OS was similar in pts exposed or not to CS (HR, 1.14; p=0.55).
The use of CS during nivolumab in mccRCC is not associated with a detrimental effect on survival outcomes. The positive association of corticosteroid use for irAEs with outcomes was not confirmed by second landmark modalities. Immortal time bias should be carefully considered when studying time-dependent variable.
NCT03013335.
UNICANCER.
Bristol-Myers Squibb.
M. Gross-Goupil: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Ipsen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis. B. Laguerre: Honoraria (self), Travel / Accommodation / Expenses: BMS; Honoraria (self), Travel / Accommodation / Expenses: Pfizer; Honoraria (self): Novartis; Honoraria (self): Ipsen. P. Barthelemy: Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Janssen-Cilag; Honoraria (self), Advisory / Consultancy: Sanofi. S. Negrier: Honoraria (self): Pfizer; Honoraria (self): Bms; Honoraria (self): Novartis; Honoraria (self): IPSEN; Honoraria (self): Euspharma. L. Geoffrois: Honoraria (self), Travel / Accommodation / Expenses: MSD; Honoraria (self), Travel / Accommodation / Expenses: BMS; Honoraria (self): Ipsen; Honoraria (self): Novartis; Travel / Accommodation / Expenses: Merck. S. Ladoire: Advisory / Consultancy, Travel / Accommodation / Expenses: BMS. M. Laramas: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: SANOFI; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer; Speaker Bureau / Expert testimony: BMS; Speaker Bureau / Expert testimony: Amgen; Speaker Bureau / Expert testimony: IPSEN; Speaker Bureau / Expert testimony: Janssen; Travel / Accommodation / Expenses: Eisai. S. Oudard: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Ipsen. B. Escudier: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Roche; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Eusa; Advisory / Consultancy, Research grant / Funding (institution): Avevo; Advisory / Consultancy, Research grant / Funding (institution): Pfizer. L. Albiges: Advisory / Consultancy, Compensated to institution: Pfizer; Advisory / Consultancy, Compensated to institution: Novartis; Advisory / Consultancy, Compensated to institution: BMS; Advisory / Consultancy, Compensated to institution: Ipsen; Advisory / Consultancy, Compensated to institution: Roche; Advisory / Consultancy, Compensated to institution: MSD; Advisory / Consultancy, Compensated to institution: AstraZeneca. All other authors have declared no conflicts of interest.
Deep‐sea hydrothermal venting is now recognized as a major source of iron (Fe), an essential trace element that controls marine productivity. However, the reactions occurring during dispersal from ...buoyant plumes to neutrally buoyant hydrothermal plumes are still poorly constrained. Here we report for the first time on the dissolved‐particulate partition of Fe after in situ filtration at the early stage of mixing at different hydrothermal discharges, i.e., Lucky Strike (37°N), TAG (26°N), and Snakepit (23°N) on the Mid‐Atlantic Ridge. We found that hydrothermal iron is almost completely preserved (>90%) in the dissolved fraction, arguing for low iron‐bearing sulfide precipitation of iron in basalt‐hosted systems with low Fe:H2S ratios. This result can only be explained by a kinetically limited formation of pyrite. The small part of Fe being precipitated as sulfides in the mixing gradient (<10%) is restricted to the inclusion of Fe in minerals of high Cu and Zn content. We also show that secondary venting is a source of Fe‐depleted hydrothermal solutions. These results provide new constrains on Fe fluxes from hydrothermal venting.
Key Points
Deep‐sea hydrothermal venting is a major but poorly constrained source of iron to the Ocean
Iron removal by sulfide precipitation at the early stage of mixing is much more limited than expected in basalt‐hosted systems
Our results have several implications for the quantification of hydrothermal iron fluxes
Biological rhythms are a fundamental property of life. The deep ocean covers 66% of our planet surface and is one of the largest biomes. The deep sea has long been considered as an arrhythmic ...environment because sunlight is totally absent below 1,000 m depth. In the present study, we have sequenced the temporal transcriptomes of a deep-sea species, the ecosystem-structuring vent mussel Bathymodiolus azoricus. We reveal that tidal cycles predominate in the transcriptome and physiology of mussels fixed directly at hydrothermal vents at 1,688 m depth at the Mid-Atlantic Ridge, whereas daily cycles prevail in mussels sampled after laboratory acclimation. We identify B. azoricus canonical circadian clock genes, and show that oscillations observed in deep-sea mussels could be either a direct response to environmental stimulus, or be driven endogenously by one or more biological clocks. This work generates in situ insights into temporal organisation in a deep-sea organism.
We have reviewed available visual information from the seafloor, and recently acquired microbathymetry for several traverses across the Lucky Strike segment, to evaluate the distribution of ...hydrothermal activity. We have identified a new on-axis site with diffuse flow, Ewan, and an active vent structure ∼1.2 km from the axis, Capelinhos. These sites are minor relative to the Main field, and our total heatflux estimate for all active sites (200–1200 MW) is only slightly higher than previously published estimates. We also identify fossil sites W of the main Lucky Strike field. A circular feature ∼200 m in diameter located on the flanks of a rifted off-axis central volcano is likely a large and inactive hydrothermal edifice, named Grunnus. We find no indicator of focused hydrothermal activity elsewhere along the segment, suggesting that the enhanced melt supply and the associated melt lenses, required to form central volcanoes, also sustain hydrothermal circulation to form and maintain large and long-lived hydrothermal fields. Hydrothermal discharge to the seafloor occurs along fault traces, suggesting focusing of hydrothermal circulation in the shallow crust along permeable fault zones.
•Two new active and two inactive hydrothermal sites at Lucky Strike segment.•Hydrothermalism linked to focused melt supply and central volcano formation.•Heatflux of new sites only ∼10% of that of the Main Lucky trike field.•Shallow crust flow along permeable faults and seafloor discharge along fault traces.
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