Stefania Gori

Multicenter Phase II Study of Lapatinib in Patients with Brain Metastases from HER2-Positive Breast Cancer

Purpose: Brain metastases develop in one third of patients with advanced HER2+ breast cancer. Effective therapy for patients with central nervous system (CNS) progression after cranial radiation is extremely limited and represents a major clinical challenge. Lapatinib, an epidermal growth factor receptor/HER2 inhibitor, was associated with regressions of CNS lesions in a small phase 2 trial. The current study was done to further evaluate the CNS activity of lapatinib. The study was later amended to allow patients who progressed on lapatinib the option of receiving lapatinib plus capecitabine. Experimental Design: Eligible patients had HER2+ breast cancer, progressive brain metastases, prior trastuzumab, and cranial radiotherapy. The primary end point was CNS objective response, defined as ≥50% volumetric reduction of CNS lesion(s) in the absence of increasing steroid use, progressive neurologic signs and symptoms, or progressive extra-CNS disease. Results: Two-hundred and forty-two patients entered the study. CNS objective responses to lapatinib were observed in 6% of patients. In an exploratory analysis, 21% of patients experienced a ≥20% volumetric reduction in their CNS lesions. An association was observed between volumetric reduction and improvement in progression-free survival and neurologic signs and symptoms. Of the 50 evaluable patients who entered the lapatinib plus capecitabine extension, 20% experienced a CNS objective response and 40% experienced a ≥20% volumetric reduction in their CNS lesions. Conclusions: This study confirms the modest CNS antitumor activity of lapatinib. Additional responses were observed with the combination of lapatinib and capecitabine. Further studies of lapatinib-based regimens for CNS metastases from HER2+ breast cancer are warranted.

CEREBEL (EGF111438): A Phase III, Randomized, Open-Label Study of Lapatinib Plus Capecitabine Versus Trastuzumab Plus Capecitabine in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer

PURPOSEnCEREBEL compared the incidence of CNS metastases as first site of relapse in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer receiving lapatinib-capecitabine or trastuzumab-capecitabine.nnnPATIENTS AND METHODSnPatients without baseline CNS metastases were randomly assigned (1:1) to receive lapatinib-capecitabine (lapatinib 1,250 mg per day; capecitabine 2,000 mg/m(2) per day on days 1 to 14 every 21 days) or trastuzumab-capecitabine (trastuzumab loading dose of 8 mg/kg followed by an infusion of 6 mg/kg every 3 weeks; capecitabine 2,500 mg/m(2) per day on days 1 to 14 every 21 days). The primary end point was incidence of CNS metastases as first site of relapse. Secondary end points included progression-free survival (PFS) and overall survival (OS).nnnRESULTSnThe study was terminated early with 540 enrolled patients (271 received lapatinib-capecitabine, and 269 received trastuzumab-capecitabine). Incidence of CNS metastases as first site of relapse was 3% (eight of 251 patients) for lapatinib-capecitabine and 5% (12 of 250 patients) for trastuzumab-capecitabine (treatment differences, -1.6%; 95% CI, -2% to 5%; P = .360). PFS and OS were longer with trastuzumab-capecitabine versus lapatinib-capecitabine (hazard ratio [HR] for PFS, 1.30; 95% CI, 1.04 to 1.64; HR for OS, 1.34; 95% CI, 0.95 to 1.64). Serious adverse events were reported in 13% (34 of 269 patients) and 17% (45 of 267 patients) of patients in the lapatinib-capecitabine and trastuzumab-capecitabine arms, respectively.nnnCONCLUSIONnCEREBEL is inconclusive for the primary end point, and no difference was detected between lapatinb-capecitabine and trastuzumab-capecitabine for the incidence of CNS metastases. A better outcome was observed with trastuzumab-capecitabine in the overall population. However, lapatinib-capecitabine efficacy may have been affected by previous exposure to a trastuzumab regimen and/or when treatment was given as first- or second-line therapy in the metastatic setting.

Neuroendocrine differentiation in breast carcinoma: clinicopathological features and outcome

Primary neuroendocrine (NE) breast carcinoma (BC) is an entity with a wide range of prevalence and poorly defined clinical behaviour. We evaluated the prevalence, clinicopathological features and clinical outcome of NEBC.

Intensity modulated radiation therapy with simultaneous integrated boost in early breast cancer irradiation. Report of feasibility and preliminary toxicity.

PURPOSEnTo investigate the feasibility and tolerance in the use of adjuvant intensity modulated radiation therapy (IMRT) and simultaneous integrated boost in patients with a diagnosis of breast cancer after breast-conserving surgery.nnnPATIENTS AND METHODSnBetween September 2011 to February 2013, 112 women with a diagnosis of early breast cancer (T1-2, N0-1, M0) were treated with IMRT and simultaneous integrated boost after breast-conserving surgery in our institution. A dose of 50Gy in 25 fractions was prescribed to the whole breast and an additional dose of radiation was prescribed on the tumour bed. A dose prescription of 60Gy in 25 fractions to the tumour bed was used in patients with negative margins after surgery, whereas if the margins were close (<1mm) or positive (without a new surgical resection) a dose of 64Gy was prescribed. All patients were followed with periodic clinical evaluation. Acute and late toxicity were scored using the EORTC/RTOG radiation morbidity score system. Both patient and physician recorded cosmetic outcome evaluation with a subjective judgment scale at the time of scheduled follow-up.nnnRESULTSnThe median follow-up was 28 months (range 24-40 months). The acute skin grade toxicity during the treatment was grade 0 in 8 patients (7%), grade 1 in 80 (72%), grade 2 in 24 cases (21%). No grade 3 or higher acute skin toxicity was observed. At 12 months, skin toxicity was grade 0 in 78 patients (70%), grade 1 in 34 patients (30%). No toxicity grade 2 or higher was registered. At 24 months, skin toxicity was grade 0 in 79 patients (71%), grade 1 in 33 patients (29%). No case of grade 2 toxicity or higher was registered. The pretreatment variables correlated with skin grade 2 acute toxicity were adjuvant chemotherapy (P=0.01) and breast volume ≥700cm(3) (P=0.001). Patients with an acute skin toxicity grade 2 had a higher probability to develop late skin toxicity (P<0.0001). In the 98% of cases, patients were judged to have a good or excellent cosmetic outcome. The 2-year-overall survival and 2-year-local control were 100%.nnnCONCLUSIONnThese data support the feasibility and safety of IMRT with simultaneous integrated boost in patients with a diagnosis of early breast cancer following breast-conserving surgery with acceptable acute and late treatment-related toxicity. A longer follow-up is needed to define the efficacy on outcomes.

Cardiotoxicity of Aromatase Inhibitors in Breast Cancer Patients

Abstract Aromatase inhibitors represent an effective endocrine treatment for patients with hormone receptor‐positive breast cancer, in early stage and in metastatic disease. However, by decreasing levels of serum estrogens they also potentially reduce the protective effect of estrogens on the cardiovascular system. Patients treated with aromatase inhibitors, in fact, compared with those who receive tamoxifen, more often develop hyperlipidemia, hypercholesterolemia, and hypertension, which are recognized risk factors for cardiovascular disease. This might raise some concerns especially in the adjuvant setting where the aim of treatment is the cure, and for postmenopausal patients who are already at risk for cardiovascular disease. However, whether the relative higher incidence of cardiac adverse events reported with aromatase inhibitors compared with tamoxifen is related to an actual cardiac toxicity of aromatase inhibitors rather than a cardioprotective effect of tamoxifen is still unclear. In this article we review the available literature on cardiotoxicity of aromatase inhibitors and provide some practical advice to improve the cardiovascular safety profile of these drugs.

Failure of dihydroartemisinin-piperaquine treatment of uncomplicated Plasmodium falciparum malaria in a traveller coming from Ethiopia

BackgroundArtemisinin combination therapy (ACT) is used worldwide as the first-line treatment against uncomplicated Plasmodium falciparum malaria. Despite the success of ACT in reducing the global burden of malaria, the emerging of resistance to artemisinin threatens its use.Case reportThis report describes the first case of failure of dihydroartemisinin-piperaquine (DHA-PPQ) for the treatment of P. falciparum malaria diagnosed in Europe. It occurred in an Italian tourist returned from Ethiopia. She completely recovered after the DHA-PPQ treatment but 32xa0days after the end of therapy she had a recrudescence. The retrospective analysis indicated a correct DHA-PPQ absorption and genotyping demonstrated that the same P. falciparum strain was responsible for the both episodes.ConclusionIn consideration of the growing number of cases of resistance to ACT, it is important to consider a possible recrudescence, that can manifest also several weeks after treatment.

Prevalence of malnutrition in patients at first medical oncology visit: the PreMiO study

Background In cancer patients, malnutrition is associated with treatment toxicity, complications, reduced physical functioning, and decreased survival. The Prevalence of Malnutrition in Oncology (PreMiO) study identified malnutrition or its risk among cancer patients making their first medical oncology visit. Innovatively, oncologists, not nutritionists, evaluated the nutritional status of the patients in this study. Methods PreMiO was a prospective, observational study conducted at 22 medical oncology centers across Italy. For inclusion, adult patients (>18 years) had a solid tumor diagnosis, were treatment-naive, and had a life expectancy >3 months. Malnutrition was identified by the Mini Nutritional Assessment (MNA), appetite status with a visual analog scale (VAS), and appetite loss with a modified version of Anorexia-Cachexia Subscale (AC/S-12) of the Functional Assessment of Anorexia-Cachexia Therapy (FAACT). Findings Of patients enrolled (N=1,952), 51% had nutritional impairment; 9% were overtly malnourished, and 43% were at risk for malnutrition. Severity of malnutrition was positively correlated with the stage of cancer. Over 40% of patients were experiencing anorexia, as reported in the VAS and FAACT questionnaire. During the prior six months, 64% of patients lost weight (1–10 kg). Interpretation Malnutrition, anorexia, and weight loss are common in cancer patients, even at their first visit to a medical oncology center.

A phase 2 study of temozolomide in pretreated metastatic colorectal cancer with MGMT promoter methylation

Background:Presently, few options are available for refractory colorectal cancer (CRC). O6-methyl-guanine-DNA-methyltransferase (MGMT) promoter methylation is a frequent and early event in CRC tumourigenesis. This epigenetic silencing is a predictor of response to the alkylating drug temozolomide in glioblastoma. Preclinical evidences and some case reports showed temozolomide activity in CRC with MGMT silencing, but the available data from clinical trials are inconsistent.Methods:This was a multicentre, phase 2 trial, planned according to a two-stage Simon’s optimal design to investigate activity and safety of temozolomide in refractory CRC harbouring MGMT promoter methylation. The primary end point was overall response rate (ORR). Patients who failed two or more prior treatments received temozolomide at a dose of 150–200u2009mgu2009m−2 per day on days 1–5 every 28 days.Results:From July 2012 to June 2016, 225 patients were screened, 80 showed MGMT promoter methylation and 41 were enrolled. Overall response rate was 10% and disease control rate was 32%. Median progression-free survival and overall survival were 1.9 and 5.1 months, respectively.Conclusions:Temozolomide showed a modest activity in this heavily pretreated population and the study did not meet its primary end point. The role of temozolomide in CRC remains still controversial and further research is warranted.

Radiation dose intensification in pre-operative chemo-radiotherapy for locally advanced rectal cancer

BackgroundTo assess the role of radiation dose intensification with simultaneous integrated boost guided by 18-FDG-PET/CT in pre-operative chemo-radiotherapy (ChT-RT) for locally advanced rectal cancer.MethodsA prospective study was approved by the Internal Review Board. Inclusion criteria were: agexa0>18xa0years old, World Health Organization performance status of 0–1, locally advanced histologically proven adenocarcinoma of the rectum within 10xa0cm of the anal verge, signed specific informed consent. High-dose volumes were defined including the hyper-metabolic areas of 18-FDG-PET/CT of primary tumor and the corresponding mesorectum and/or pelvic nodes with at least a standardized uptake values (SUV) of 5. A dose of 60xa0Gy/30 fractions was delivered. A total dose of 54xa0Gy/30 fractions was delivered to prophylactic areas. Capecitabine was administered concomitantly with RT for a dose of 825xa0mg/mq twice daily for 5xa0days/every week.ResultsBetween September 2011 and July 2015 fortypatients were recruited. At the time of the analysis, median follow up was 20xa0months (range 5–51). The median interval from the end of ChT-RT to surgery was 9xa0weeks (range 8–12). Thirty-seven patients (92.5xa0%) were submitted to sphincter preservation. Tumor Regression Grade (Mandard scale) was recorded as follows: grade 1 in 7 (17.5xa0%), grade 2 in 17 (42.5xa0%), grade 3 in 15 (37.5xa0%) and grade 4 in 1 (2.5xa0%). Post-surgical circumferential resection margin was negative in all patients. A tumor downstaging was reported in 62.5xa0% (95xa0% CI: 0.78–0.47). A nodes downstaging was registered in 85xa0% (95xa0% CI: 0.55–0.25). 18-FDG-PET/CT was not able to predict pCR. No correlation was found between pre-treatment SUV-max values and pCR. A metabolic tumor volumexa0>127xa0cc was related to ypTxa0≥2 (p 0.01). Patients with TRGxa0>2 had higher tumor lesion glycolysis values (p 0.05).ConclusionPreliminary results did not confirm some advantages in terms of primary tumor downstaging/downsizing compared to conventional schedules reported in historical series. The role of 18-FDG-PET/CT in neoadjuvant rectal cancer management needs to be confirmed in further investigations. Long terms results are necessary.

Fentanyl pectin nasal spray for painful mucositis in head and neck cancers during intensity-modulated radiation therapy with or without chemotherapy.

AbstractPurposeThe aim of the current analysis was to evaluate the effectiveness and tolerability of rapid onset opioid in a cohort of head and neck cancer (HNC) patients affected by painful mucositis influencing swallowing function during RTxa0±xa0ChT with definitive or adjuvant intent.MethodsA retrospective analysis was conduct on HNC patients during RTxa0±xa0ChT that received fentanyl pectin nansal spray (FPNS) for incidental BTP due to painful mucositis 13xa0min before the main meals. The period of observation has been 90xa0days starting from the beginning of RTxa0±xa0ChT.ResultsForty HNC patients with incidental BTP due to painful mucositis treated with FPNS were analyzed. The mean NRS of untreated episodes of BTP was 5.73xa0±xa01.54 decreasing to 2.25xa0±xa02.45 with FPNS (median dose 100xa0mcg). During the pain treatment, the number of meals increased from 2.08xa0±xa00.35 to 2.868xa0±xa00.4 (pxa0=xa00.000), and the BMI remained stable (from 25.086xa0±xa03.292 to 25.034xa0±xa03.090; pxa0=xa00.448). The 94.9% of patients was satisfied or very satisfied for the rapidity of the effect, and 97.4% for the easiness and convenience in the use.ConclusionsFPNS showed an acceptable safety activity profile in predictable BTP due to painful mucositis in HNC patients during RTxa0±xa0ChT. FPNS was also effective in reducing the mucositis sequelae and allowing the completion of RT scheduled scheme. Moreover, patients declared satisfaction in terms of ease of use.