Time course and management of key adverse events during the randomized phase III SOLAR-1 study of PI3K inhibitor alpelisib plus fulvestrant in patients with HR-positive advanced breast cancer.

BACKGROUND: Alpelisib (α-selective phosphatidylinositol 3-kinase inhibitor) plus fulvestrant is approved in multiple countries for men and postmenopausal women with PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer following progression on or after endocrine therapy. A detailed understanding of alpelisib's safety profile should inform adverse event (AE) management and enhance patient care. PATIENTS AND METHODS: AEs in the phase III SOLAR-1 trial were assessed in patients with and without PIK3CA mutations. The impact of protocol-specified AE-management recommendations was evaluated, including an amendment to optimize hyperglycemia and rash management. RESULTS: Patients were randomly assigned to receive fulvestrant plus alpelisib (n = 284) or placebo (n = 287). The most common grade 3/4 AEs with alpelisib were hyperglycemia (grade 3, 32.7%; grade 4, 3.9%), rash (grade 3, 9.9%), and diarrhea (grade 3, 6.7%). Median time to onset of grade ≥3 toxicity was 15 days (hyperglycemia, based on fasting plasma glucose), 13 days (rash), and 139 days (diarrhea). Metformin alone or in combination with other antidiabetic agents was used by most patients (87.1%) with hyperglycemia. Preventive anti-rash medication resulted in lower incidence (any grade, 26.7% versus 64.1%) and severity of rash (grade 3, 11.6% versus 22.7%) versus no preventative medication. Discontinuations due to grade ≥3 AEs were lower following more-detailed AE management guidelines (7.9% versus 18.1% previously). Patients with PIK3CA mutations had a median alpelisib dose intensity of 248 mg/day. Median progression-free survival with alpelisib was 12.5 and 9.6 months for alpelisib dose intensities of ≥248 mg/day and <248 mg/day, respectively, compared with 5.8 months with placebo. CONCLUSIONS: Hyperglycemia and rash occurred early during alpelisib treatment, while diarrhea occurred at a later time point. Early identification, prevention, and intervention, including concomitant medications and alpelisib dose modifications, resulted in less severe toxicities. Reductions in treatment discontinuations and improved progression-free survival at higher alpelisib dose intensities support the need for optimal AE management. CLINICALTRIALS. GOV ID: NCT02437318.

Sequential chemotherapy regimen of induction with panitumumab and paclitaxel followed by radiotherapy and panitumumab in patients with locally advanced head and neck cancer unfit for platinum derivatives. The phase II, PANTERA/TTCC-2010-06 study.

BACKGROUND: Sequential treatment of Panitumumab (Pb) plus Paclitaxel (Px) as induction treatment (IT) followed by concurrent bioradiotherapy (Bio-RT) with Pb may be an alternative for locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) in patients ineligible for high-dose cisplatin therapy. METHODS: Phase II, single-arm, multicentre study, with two-stage design, in patients ≥ 18 years with stage III-IVa-b LA-SCCHN unfit for platinum. Patients received Px + Pb (9 weeks) as IT followed by Bio-RT + Pb. Primary endpoint: overall response rate (ORR) after IT, defined as: more than 70% of patients achieving complete response (CR) or partial response (PR) to IT. Secondary end-points: progression-free survival, organ preservation rate, safety profile. RESULTS: Study ended prematurely (51 patients) due to slow recruitment. ORR: 66.7% (95% CI: 53.7-79.6), 8 (15.7%) CR and 26 (51.0%) PR. 39 patients (76%) completed radiotherapy (RT). Pb and/or Px-related adverse events (AEs) grade 3-4: 56.9% during IT and 63.4% during the concomitant phase, of which most common were skin toxicity (33.3%). Five deaths occurred during treatment, two of them (3.9%) were Pb and/or Px-related. CONCLUSIONS: Although underpowered, ORR was higher than the pre-specified boundary for considering the treatment active. Although Px + Pb as IT provides some benefit, the safety profile is worse than expected. To consider Pb + Px as IT as an alternative for platinum-unsuitable LA-SCCHN, further research/investigation would be needed.

[Myasthenia and thymoma in a seven year old girl]. / Miastenia y timoma en una niña de 7 años.

INTRODUCTION: Myasthenia is an autoimmune disease, being generalized muscular weakness, with important participation of facial muscles, a prominent feature. Signs of muscular fatigue arise, worsened by exercise and alleviated by rest. Clinical symptoms are less marked before noon, and get worse as the day advances, through the afternoon and evening. A clear relationship between myasthenia and thymic abnormalities does exist, being glandular hyperplasia and tumours the commonest underlying pathologic findings. Initial treatment is based on anticholinesterase drugs and steroids. Non respondents should be treated with immunoglobulins, immunosuppresses, plasmapheresis and surgical removal of the thymus, according to the symptoms control. CASE REPORT: We present the case of a seven years old girl with generalized muscular weakness, worsening through the day, being the diagnosis of myasthenia confirmed by the high level of acetylcholine antireceptors antibodies and the neurophysiologic study. Imaging study of the mediastinum showed a thymic mass located in the right lobe. CONCLUSION: It is therefore most important to rule out these conditions when myasthenia is suspected.

[Partial delegation to radiation therapists of the control by onboard imaging of patient positioning]. / Délégation partielle du contrôle de position du patient par imagerie embarquée aux manipulateurs en électroradiologie.

PURPOSE: Daily set up of patients with prostate cancer using orthogonal kV/kV imaging and weekly set up control require 1h to 1h30 of off line revision by a radio-oncologist per day and per accelerator. The aim of this study was to evaluate the possibility to delegate this control to radiation therapists. MATERIAL AND METHODS: The files of 33 patients (including 13 with prostate cancer) treated from November 2010 to February 2011 on a Varian™ Clinac IX accelerator with an OBI™ system were evaluated. Radiation therapists made the daily kV/kV imaging. Radiation therapists made the online control by kV/kV for patient repositioning and radio-oncologists made the offline reviews; the results were compared and analysed (seven radiation therapists and seven radio-oncologists). For an isocentre displacement of 5mm, the radiation therapist had to call the radio-oncologist to make a medical decision (treatment or patient displacement). The difference of measures and the concordance of decisions between radiation therapists and radio-oncologists were calculated. RESULTS: Five hundred and fifty-six measures were made for 33 treatments, including 226 measures for prostate cancer treatment. The difference of measures between radiation therapists and radio-oncologists was 3mm or less in 93.7% for all treatments and 96.2% for prostate cancer treatment. The concordance of decision between radiation therapists and radio-oncologists for measures up to 4mm was 97% (CI95±2%) vs. 57% (CI95±10%) for measures equal to or higher than 5mm (P<0.0001). CONCLUSION: Radiation therapists are able to do daily set up using kV/kV on the bony structures of patients with prostate cancer, with a risk of disagreement higher than 3mm less than 4%. The weekly set up controls (different primaries) can be delegated to the radiation therapists, subject to an accurate procedure using a medical alert for a given threshold. Training and competence certification are required to secure the process.

[Target volume delineation for head and neck cancer intensity-modulated radiotherapy]. / Délinéation des volumes cibles des cancers des voies aérodigestives supérieures en radiothérapie conformationnelle avec modulation d'intensité

This article describes the determination and the delineation of the target volumes for head-and-neck cancers treated with intensity-modulated radiotherapy (IMRT). The delineation of the clinical target volumes (CTV) on the computerized tomography scanner (CT scan) requires a rigorous methodology due to the complexity of head-and-neck anatomy. The clinical examination with a sketch of pretreatment tumour extension, the surgical and pathological reports and the adequate images (CT scan, magnetic resonance imaging and fluorodeoxyglucose positron emission tomography) are necessary for the delineation. The target volumes depend on the overall strategy: sequential IMRT or simultaneous integrated boost-IMRT (SIB-IMRT). The concept of selectivity of the potential subclinical disease near the primary tumor and the selection of neck nodal targets are described according to the recommendations and the litterature. The planing target volume (PTV), mainly reflecting setup errors (random and systematic), results from a uniform 4-5mm expansion around the CTV. We propose the successive delineation of: (1) the gross volume tumour (GTV); (2) the "high risk" CTV1 around the GTV or including the postoperative tumour bed in case of positive margins or nodal extracapsular spread (65-70 Gy in 30-35 fractions); (3) the CTV2 "intermediate risk" around the CTV1 for SIB-IMRT (59-63 Gy in 30-35 fractions); (4) the "low-risk" CTV3 (54-56 Gy in 30-35 fractions); (5) the PTVs.

[Hypopharynx and larynx cancers: propositions for the selection and the delineation of peritumoral microscopic disease volumes (lymph nodes excluded)]. / Cancer de l'hypopharynx et du larynx : proposition de sélection et délimitation des volumes cibles microscopiques péri-tumoraux (aires ganglionnaires exclues).

This article reviews the concept of selectivity in peritumoral microscopic disease to be included in the Clinical Target Volume (CTV) for elective treatment for larynx and hypopharynx squamous cell carcinoma (50 Gy or 54-60 Gy for SIB-IMRT), using the local tumoral spread. The objective of the present article is to present the different delineations of the target volumes, required for an appropriate application of 3-DCRT and IMRT (supraglottic larynx, vocal cord, subglottic larynx, pyriform sinus, lateral and posterior pharyngeal wall and postcricoid pharynx). These propositions are for the delineation of microscopic peritumoral target volumes when external beam irradiation is required. CTVs are illustrated on CT sections.

[Prospective study with auditory evoked potentials of the brain stem in children at risk]. / Estudio prospectivo con potenciales evocados auditivos de tronco cerebral en niños de riesgo.

OBJECTIVE: The aim of this study was to evaluate methods of hypoacusis screening. PATIENTS AND METHODS: The early detection of audition problems is vital for quick rehabilitation. For this reason, resting on the criteria of the Comisión Española para la Detección Precoz de la Hipoacusia (Spanish Commission for the Early Detection of Hypoacusis), we have carried out a prospective study, from January to May 1998, evaluating patients at risk of suffering from hypoacusis. The study included 151 patients with ages between birth and 14 years. Medical records and brainstem auditory evoked responses (BAER) were carried out. RESULTS: The most common reason for requesting a consultation for the 151 patients included in our study was the suspicion of hypoacusis. Seventy-one (47%) presented pathological BAER, 37 of them were bilateral. In most cases the loss of audition was of cochlear origin, with 11 patients having a serious deafness, 4 with bilateral affection (3 suspicious of hypoacusis and 1 of hyperbilirubinemia) and 7 unilateral deafness. CONCLUSIONS: BAER is a good screening method for children at risk. It is an innocuous, objective and specific test that does not require the patient's collaboration. The level of positives is high (47%).