Nilotinib compassionate use in advanced GIST : a retrospective analysis

Introduction: Tyrosine kinase inhibitors (TKI) have considerably improved outcome of patients with advanced GIST and extended overall survival to more than 5 years. Yet, the median progression-free survival is approximately 2 years with first-line imatinib and 24 weeks with second-line sunitinib, which calls for treatment alternatives. Nilotinib is a second-generation TKI with at least similar inhibitory activity as imatinib. A Phase I study has shown that nilotinib monotherapy has clinical activity in GIST. Methods: After failure of all available therapeutic options patients had access to nilotinib on a compassionate use (CU) programm. Nilotinib was started at a dose of 400 mg bid, with dose reduction to 400mg qd allowed in the case of toxicity. 94 pts were approved for nilotinib CU in 10 European countries. We herein present retrospective data of 42 pts from 5 European countries treated in 11 centers. Results: Median age at nilotinib treatment start was 59 years (median; range 24-79 y). 30 of 42 patients were male. Most pts had metastatic disease of gastric origin at initial diagnosis. KIT exon 11 mutations were most frequent. The median number of surgical resections was 1 (range 0-8). All pts had failed both imatinib and sunitinib before nilotinib, and few had also received additional investigational treatments. Nilotinib was well tolerated, and discontinued due to toxicity in 15% only. Median follow-up is 176 days (range 15-876 d). Nilotinib treatment duration is 75 days (median; range 3-727 d). Partial remission with nilotinib treatment was seen in 11% of pts. Median OS was 263 days (Kaplan-Meier). Conclusion: This is the largest series reported assessing efficacy of nilotinib for imatinib- and sunitinib-refractory GIST reported yet. Nilotinib displays significant clinical activity in this heavily pretreated group of pts. These results warrant further investigation of nilotinib in GIST, including its use in first or second-line treatment. Patient and data collection is ongoing, updated results will be presented.

Concomitant chemoradiotherapy versus acceleration of radiotherapy with or without concomitant chemotherapy in locally advanced head and neck carcinoma (GORTEC 99-02): an open-label phase 3 randomised trial.

BACKGROUND: Concomitant chemoradiotherapy and accelerated radiotherapy independently improve outcomes for patients with locally advanced head and neck squamous-cell carcinoma (HNSCC). We aimed to assess the efficacy and safety of a combination of these approaches. METHODS: In our open-label phase 3 randomised trial, we enrolled patients with locally advanced, stage III and IV (non-metastatic) HNSCC and an Eastern Cooperative Oncology Group performance status of 0-2. We randomly allocated patients centrally with a computer program (with centre, T stage, N stage, and localisation as minimisation factors) in a 1:1:1 ratio to receive conventional chemoradiotherapy (70 Gy in 7 weeks plus three cycles of 4 days' concomitant carboplatin-fluorouracil), accelerated radiotherapy-chemotherapy (70 Gy in 6 weeks plus two cycles of 5 days' concomitant carboplatin-fluorouracil), or very accelerated radiotherapy alone (64·8 Gy [1·8 Gy twice daily] in 3·5 weeks). The primary endpoint, progression-free survival (PFS), was assessed in all enrolled patients. This trial is completed. The trial is registered with ClinicalTrials.gov, number NCT00828386. FINDINGS: Between Feb 29, 2000, and May 9, 2007, we randomly allocated 279 patients to receive conventional chemoradiotherapy, 280 to accelerated radiotherapy-chemotherapy, and 281 to very accelerated radiotherapy. Median follow-up was 5·2 years (IQR 4·9-6·2); rates of chemotherapy and radiotherapy compliance were good in all groups. Accelerated radiotherapy-chemotherapy offered no PFS benefit compared with conventional chemoradiotherapy (HR 1·02, 95% CI 0·84-1·23; p=0·88) or very accelerated radiotherapy (0·83, 0·69-1·01; p=0·060); conventional chemoradiotherapy improved PFS compared with very accelerated radiotherapy (0·82, 0·67-0·99; p=0·041). 3-year PFS was 37·6% (95% CI 32·1-43·4) after conventional chemoradiotherapy, 34·1% (28·7-39·8) after accelerated radiotherapy-chemotherapy, and 32·2% (27·0-37·9) after very accelerated radiotherapy. More patients in the very accelerated radiotherapy group had RTOG grade 3-4 acute mucosal toxicity (226 [84%] of 268 patients) compared with accelerated radiotherapy-chemotherapy (205 [76%] of 271 patients) or conventional chemoradiotherapy (180 [69%] of 262; p=0·0001). 158 (60%) of 265 patients in the conventional chemoradiotherapy group, 176 (64%) of 276 patients in the accelerated radiotherapy-chemotherapy group, and 190 (70%) of 272 patients in the very accelerated radiotherapy group were intubated with feeding tubes during treatment (p=0·045). INTERPRETATION: Chemotherapy has a substantial treatment effect given concomitantly with radiotherapy and acceleration of radiotherapy cannot compensate for the absence of chemotherapy. We noted the most favourable outcomes for conventional chemoradiotherapy, suggesting that acceleration of radiotherapy is probably not beneficial in concomitant chemoradiotherapy schedules. FUNDING: French Ministry of Health.

Mycosis fungoides in a lung transplant recipient with advanced ciclosporin nephropathy: management with mechlorethamine and subsequent renal transplantation.

Posttransplant cutaneous T cell lymphomas are rare and have been reported to have a poor prognosis. We report the case of a follicular mycosis fungoides in a lung transplant recipient who was successfully treated with topical mechlorethamine, prior to subsequent renal transplantation.

A phase 2 randomized trial of radiotherapy (RT) plus panitumumab compared to chemoradiotherapy in patients with unresected, locally advanced squamous cell carcinoma of the head and neck (SCCHN): interim pooled safety analysis

Background: Panitumumab (pmab), a fully human monoclonal antibody against the epidermal growth factor receptor (EGFR), is indicated as monotherapy for treatment of metastatic colorectal cancer. This ongoing study is designed to assess the efficacy and safety of pmab in combination with radiotherapy (PRT) compared to chemoradiotherapy (CRT) as initial treatment of unresected, locally advanced SCCHN (ClinicalTrials.gov Identifier: NCT00547157). Methods: This is a phase 2, open-label, randomized, multicenter study. Eligible patients (pts) were randomized 2:3 to receive cisplatin 100 mg/m2 on days 1 and 22 of RT or pmab 9.0 mg/kg on days 1, 22, and 43. Accelerated RT (70 to 72 Gy − delivered over 6 to 6.5 weeks) was planned for all pts and was delivered either by intensity-modulated radiation therapy (IMRT) modality or by three-dimensional conformal (3D-CRT) modality. The primary endpoint is local-regional control (LRC) rate at 2 years. Key secondary endpoints include PFS, OS, and safety. An external, independent data monitoring committee conducts planned safety and efficacy reviews during the course of the trial. Results: Pooled data from this planned interim safety analysis includes the first 52 of the 150 planned pts; 44 (84.6%) are male; median (range) age is 57 (33−77) years; ECOG PS 0: 65%, PS 1: 35%; 20 (39%) pts received IMRT, and 32 (61%) pts received 3D-CRT. Fifty (96%) pts completed RT, and 50 pts received RT per protocol without a major deviation. The median (range) total RT dose administered was 72 (64−74) Gy. The most common grade _ 3 adverse events graded using the CTCAE version 3.0 are shown (Table). Conclusions: After the interim safety analysis, CONCERT-2 continues per protocol. Study enrollment is estimated to be completed by October 2009.

Saturable metabolism of continuous high-dose ifosfamide with mesna and GM-CSF: a pharmacokinetic study in advanced sarcoma patients. Swiss Group for Clinical Cancer Research (SAKK).

BACKGROUND: The aim of this study was to assess the pharmacology, toxicity and activity of high-dose ifosfamide mesna +/- GM-CSF administered by a five-day continuous infusion at a total ifosfamide dose of 12-18 g/m2 in adult patients with advanced sarcomas. PATIENTS AND METHODS: Between January 1991 and October 1992 32 patients with advanced or metastatic sarcoma were entered the study. Twenty-seven patients were pretreated including twenty-three with prior ifosfamide at less than 8 g/m2 total dose/cycle. In 25 patients (27 cycles) extensive pharmacokinetic analyses were performed. RESULTS: The area under the plasma concentration-time curve (AUC) for ifosfamide increased linearly with dose while the AUC's of the metabolites measured in plasma by thin-layer chromatography did not increase with dose, particularly that of the active metabolite isophosphoramide mustard. Furthermore the AUC of the inactive carboxymetabolite did not increase with dose. Interpatient variability of pharmacokinetic parameters was high. Dose-limiting toxicity was myelosuppression at 18 g/m2 total dose with grade 4 neutropenia in five of six patients and grade 4 thrombocytopenia in four of six patients. Therefore the maximum tolerated dose was considered to be 18 g/m2 total dose. There was one CR and eleven PR in twenty-nine evaluable patients (overall response rate 41%). CONCLUSION: Both the activation and inactivation pathways of ifosfamide are non-linear and saturable at high-doses although the pharmacokinetics of the parent drug itself are dose linear. Ifosfamide doses greater than 14-16 g/m2 per cycle appear to result in a relative decrease of the active metabolite isophosphoramide mustard. These data suggest a dose-dependent saturation or even inhibition of ifosfamide metabolism by increasing high dose ifosfamide and suggest the need for further metabolic studies.

Development of targeted therapies in advanced gastric cancer: promising exploratory steps in a new era.

PURPOSE OF REVIEW: Many chemotherapeutic drugs, including fluoropyrimidines, platinums, CPT-11, taxanes and adriamycin have single-agent activity in advanced gastric cancer. Although combination chemotherapy has been shown to be more effective than single agents, response rates between 30 and 50% have not fulfilled their promise as progression-free survival from the best combinations ranges between 3 and 7 months and overall survival between 8 and 11 months. The development of targeted therapies in gastric cancer clearly stays behind the integration of these novel agents into new treatment concepts for patients with colorectal cancer. This review summarizes the experience and major recent advances in the development of targeted therapies in advanced gastric cancer. RECENT FINDINGS: Recent publications on targeted therapies in gastric cancer are limited to nonrandomized phase I or II trials. The majority of agents tested were angiogenesis inhibitors or agents targeting the epidermal growth factor receptors epidermal growth factor receptor 1 and HER2. SUMMARY: Adequately powered, randomized phase III trials are necessary to define the clinical role of targeted therapies in advanced gastric cancer. Biomarker studies to correlate with treatment outcomes will be critical to identify patients who benefit most from chemotherapy and targeted therapy.

Occurrence of sectoral choroidal occlusive vasculopathy and retinal arteriolar embolization after superselective ophthalmic artery chemotherapy for advanced intraocular retinoblastoma.

BACKGROUND: : Superselective ophthalmic artery chemotherapy (SOAC) has recently been proposed as an alternative to intravenous chemoreduction for advanced intraocular retinoblastoma. Preliminary results appear promising in terms of tumor control and eye conservation, but little is known regarding ocular toxicity and visual prognosis. In this study, we report on the vascular adverse effects observed in our initial cohort of 13 patients. METHODS: : The charts of 13 consecutive patients with retinoblastoma who received a total of 30 injections (up to 3 injections of a single agent per patient at 3-week interval) of melphalan (0.35 mg/kg) in the ophthalmic artery between November 2008 and June 2010 were retrospectively reviewed. RetCam fundus photography and fluorescein angiography were performed at presentation and before each injection. Vision was assessed at the latest visit. RESULTS: : Enucleation and external beam radiotherapy could be avoided in all cases but one, with a mean follow-up of 7 months. Sectoral choroidal occlusive vasculopathy leading to chorioretinal atrophy was observed temporally in 2 eyes (15%) 3 weeks to 6 weeks after the beginning of SOAC and retinal arteriolar emboli in 1 eye 2 weeks after injection. There was no stroke or other clinically significant systemic side effects except a perioperative transient spasm of the internal carotid artery in one patient. Vision ranged between 20/1600 and 20/32 depending on the status of the macula. CONCLUSION: : Superselective ophthalmic artery chemotherapy was effective in all patients with no stroke or other systemic vascular complications. Unlike intravenous chemoreduction, SOAC is associated with potentially sight-threatening adverse effects, such as severe chorioretinal atrophy secondary to subacute choroidal occlusive vasculopathy or central retinal artery embolism, not to mention the risk of ophthalmic artery obstruction, which was not observed in this series. Further analysis of the risks and benefits of SOAC will define its role within the therapeutic arsenal. Meanwhile, we suggest that SOAC should be given in one eye only and restricted to advanced cases of retinoblastoma, as an alternative to enucleation and/or external beam radiotherapy.

Cetuximab in combination with chemoradiotherapy prior to surgery in patients with resectable, locally advanced esophageal carcinoma : a prospective, multicenter phase lb-ll trial of the Swiss Group for Clinical Cancer Research (SAKK 75/06) : 4570

Background: Cetuximab significantly enhances efficacy of radiotherapy and chemotherapy in head and neck cancer. We investigated the safety and feasibility of adding cetuximab to neoadjuvant chemoradiation of locally advanced esophageal cancer. Methods: Pts with resectable, locally advanced squamous cell carcinoma (SCC) or adenocarcinoma (AC) of the thoracic esophagus or gastroesophageal junction (staged by EUS, CT and PET scan) were treated with 2 cycles of induction chemotherapy (docetaxel 75mg/m2, cisplatin 75mg/m2 q3w and weekly cetuximab 250mg/m2), followed by concomitant chemo- immuno-radiation therapy (CIRT: docetaxel 20mg/m2, cisplatin 25mg/m2 and cetuximab 250mg/m2 weekly five times concomitant with 45 Gy radiotherapy in 25 fractions); followed by surgery 4-8 weeks later. The phase I part consisted of 2 cohorts of 7 patients each, without and with docetaxel during CIRT, respectively. Interpatient dose-escalation (adding docetaxel during CIRT) was possible if < 2 out of 7 pts of the 1st cohort experienced limiting toxicity. Having finished the phase 1 part, 13 additional patients were treated with docetaxel-containing CIRT in a phase II part. Pathological response was evaluated according to the Mandard classification. Results: 27 pts from 12 institutions were included. As of today, results from 20 pts are available (cohort 1: 7, cohort 2: 7, phase ll : 6). Median age was 64yrs (range 47-71). 11 AC; 9 SCC. 19 pts (95%) completed CIRT (1 pt stopped treatment during induction therapy due to sepsis). 17 pts underwent resection (no surgery: 1pt for PD, 1pt for cardiac reasons). Grade 3 toxicities during CIRT included anorexia 15%, dysphagia/esophagitis 15%, fatigue 10%, nausea 10%, pruritus 5%, dehydration 5%, nail changes 5% and rash 5% .1 pt suffered from pulmonary embolism. 13 pts (65%, intention-to-treat) showed a complete or near complete pathological remission (cohort 1: 5, cohort 2: 4, phase II: 4). Conclusions: Adding cetuximab to preoperative chemoradiation for esophageal cancer is safe and feasible in a community-based multicenter setting. Antineoplastic activity is encouraging with 65% pathological responders.

Prediction of difficult intubation with advanced face recognition techniques: a preliminary study

Introduction: Difficult tracheal intubation remains a constant and significant source of morbidity and mortality in anaesthetic practice. Insufficient airway assessment in the preoperative period continues to be a major cause of unanticipated difficult intubation. Although many risk factors have already been identified, preoperative airway evaluation is not always regarded as a standard procedure and the respective weight of each risk factor remains unclear. Moreover the predictive scores available are not sensitive, moderately specific and often operator-dependant. In order to improve the preoperative detection of patients at risk for difficult intubation, we developed a system for automated and objective evaluation of morphologic criteria of the face and neck using video recordings and advanced techniques borrowed from face recognition. Method and results: Frontal video sequences were recorded in 5 healthy volunteers. During the video recording, subjects were requested to perform maximal flexion-extension of the neck and to open wide the mouth with tongue pulled out. A robust and real-time face tracking system was then applied, allowing to automatically identify and map a grid of 55 control points on the face, which were tracked during head motion. These points located important features of the face, such as the eyebrows, the nose, the contours of the eyes and mouth, and the external contours, including the chin. Moreover, based on this face tracking, the orientation of the head could also be estimated at each frame of the video sequence. Thus, we could infer for each frame the pitch angle of the head pose (related to the vertical rotation of the head) and obtain the degree of head extension. Morphological criteria used in the most frequent cited predictive scores were also extracted, such as mouth opening, degree of visibility of the uvula or thyreo-mental distance. Discussion and conclusion: Preliminary results suggest the high feasibility of the technique. The next step will be the application of the same automated and objective evaluation to patients who will undergo tracheal intubation. The difficulties related to intubation will be then correlated to the biometric characteristics of the patients. The objective in mind is to analyze the biometrics data with artificial intelligence algorithms to build a highly sensitive and specific predictive test.

Vision suisse romande de la pratique infirmière avancée [Advanced nursing practice: vision in Switzerland].

To meet the challenges related to the development of health problems taking into account the development of knowledge, several innovations in care are being implemented. Among these, advanced nursing roles and increased interprofessional collaboration are considered as important features in Switzerland. Although the international literature provides benchmarks for advanced roles, it was considered essential to contextualize these in order to promote their application value in Switzerland. Thus, from 79 statements drawn from the literature, 172 participants involved in a two-sequential phases study only kept 29 statements because they considered they were relevant, important and applicable in daily practice. However, it is important to point out that statements which have not been selected at this stage to describe advanced practice cannot be considered irrelevant permanently. Indeed, given the emergence of advanced practice in western Switzerland, it is possible that a statement judged not so relevant at this moment of the development of advanced practice, will be considered as such later on. The master's program in nursing embedded at the University of Lausanne and the University of Applied Sciences Western Switzerland was also examined in the light of these statements. It was concluded that all the objectives of the program are aligned with the competencies statements that were kept.

An EORTC phase I itudy of bortezomib in combination with oxaliplatin, leucovorin and 5-fluorouracil in patients with advanced colorectal cancer.

The combination of oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX-4) is still a reference regimen in advanced colorectal cancer; however, the addition of new biologic compounds represents a significant way forward. Bortezomib is an inhibitor of proteasome, a multicatalytic enzyme complex that degrades several intracellular proteins. In this study, escalating doses of Bortezomib were administered along with the standard FOLFOX-4 doses, in order to evaluate the dose-limiting toxicity (DLT), toxicity profile and activity of the combination. Patients with advanced colorectal cancer, unpretreated for metastatic disease, were enroled in the study. Bortezomib starting dose was 1.3mg/m(2), which was to be escalated in the subsequent steps according to the toxicities observed after first cycle. Exploratory pharmacogenetics research was conducted by analysing the association between clinical outcomes and polymorphisms in candidate genes for response to each of the used drugs. Correlation between tumour marker changes and response was also investigated. One mg/m(2) (DL-1) was defined as being the maximum tolerated dose since only 1 DLT was observed in 6 patients. The main toxicities were haematologic, neuropathy, diarrhoea and fatigue. Amongst 13 evaluable patients, five had a partial response, five had a stable disease and three patients progressed. Two patients are long-term survivors after a combined chemosurgical approach. Further trials of the current combination may be justified.