Phase I/II trial of carboplatin and paclitaxel chemotherapy in combination with intravenous oncolytic reovirus in patients with advanced malignancies

Purpose: Reovirus type 3 Dearing (RT3D) replicates preferentially in Ras-activated cancers. RT3D shows synergistic in vitro cytotoxicity in combination with platins and taxanes. The purpose of this phase I/II study was to assess RT3D combined with carboplatin/paclitaxel in patients with advanced cancers. Experimental Design: Patients were initially treated in a dose-escalating, phase I trial with intravenous RT3D days 1 to 5, carboplatin [area under curve (AUC) 5, day 1] and paclitaxel (175 mg/m2, day 1) 3-weekly. RT3D was escalated through three dose levels: 3 × 109, 1 × 1010, and 3 × 1010 TCID50 in cohorts of three. Primary endpoints were to define the maximum tolerated dose and dose-limiting toxicity and to recommend a dose for phase II studies. Secondary endpoints included pharmacokinetics, immune response, and antitumor activity. A subsequent phase II study using the 3 × 1010 TCID50 dose characterized the response rate in patients with head and neck cancer. Results: Thirty-one heavily pretreated patients received study therapy. There were no dose-limiting toxicities during dose-escalation and most toxicities were grade I/II. Overall effectiveness rates were as follows: one patient had a complete response (3.8%), six patients (23.1%) had partial response, two patients (7.6%) had major clinical responses clinically evaluated in radiation pretreated lesions which are not evaluable by Response Evaluation Criteria in Solid Tumors (RECIST), nine patients (34.6%) had stable disease, and eight patients (30.8%) had disease progression. Viral shedding was minimal and antiviral immune responses were attenuated compared with previous single-agent data for RT3D. Conclusions: The combination of RT3D plus carboplatin/paclitaxel is well tolerated with evidence of activity in cancer of the head and neck. A randomized phase III study is currently open for recruitment

Phase I/II Trial of Carboplatin and Paclitaxel Chemotherapy in Combination with Intravenous Oncolytic Reovirus in Patients with Advanced Malignancies

Purpose: Reovirus type 3 Dearing (RT3D) replicates preferentially in Ras-activated cancers. RT3D shows synergistic in vitro cytotoxicity in combination with platins and taxanes. The purpose of this phase I/II study was to assess RT3D combined with carboplatin/paclitaxel in patients with advanced cancers. Experimental Design: Patients were initially treated in a dose-escalating, phase I trial with intravenous RT3D days 1 to 5, carboplatin [area under curve (AUC) 5, day 1] and paclitaxel (175 mg/m2, day 1) 3-weekly. RT3D was escalated through three dose levels: 3 × 109, 1 × 1010, and 3 × 1010 TCID50 in cohorts of three. Primary endpoints were to define the maximum tolerated dose and dose-limiting toxicity and to recommend a dose for phase II studies. Secondary endpoints included pharmacokinetics, immune response, and antitumor activity. A subsequent phase II study using the 3 × 1010 TCID50 dose characterized the response rate in patients with head and neck cancer. Results: Thirty-one heavily pretreated patients received study therapy. There were no dose-limiting toxicities during dose-escalation and most toxicities were grade I/II. Overall effectiveness rates were as follows: one patient had a complete response (3.8%), six patients (23.1%) had partial response, two patients (7.6%) had major clinical responses clinically evaluated in radiation pretreated lesions which are not evaluable by Response Evaluation Criteria in Solid Tumors (RECIST), nine patients (34.6%) had stable disease, and eight patients (30.8%) had disease progression. Viral shedding was minimal and antiviral immune responses were attenuated compared with previous single-agent data for RT3D. Conclusions: The combination of RT3D plus carboplatin/paclitaxel is well tolerated with evidence of activity in cancer of the head and neck. A randomized phase III study is currently open for recruitment

The Cognitive Foundations of Fictional Stories

We hypothesize that fictional stories are highly successful in human cultures partly because they activate evolved cognitive mechanisms, for instance for finding mates (e.g., in romance fiction), exploring the world (e.g., in adventure and speculative fiction), or avoiding predators (e.g., in horror fiction). In this paper, we put forward a comprehensive framework to study fiction through this evolutionary lens. The primary goal of this framework is to carve fictional stories at their cognitive joints using an evolutionary framework. Reviewing a wide range of adaptive variations in human psychology – in personality and developmental psychology, behavioral ecology, and evolutionary biology, among other disciplines –, this framework also addresses the question of interindividual differences in preferences for different features in fictional stories. It generates a wide range of predictions about the patterns of combinations of such features, according to the pattenrs of variations in the mechanisms triggered by fictional stories. As a result of a highly collaborative effort, we present a comprehensive review of evolved cognitive mechanisms that fictional stories activate. To generate this review, we (1) listed more than 70 adaptive challenges humans faced in the course of their evolution, (2) identified the adaptive psychological mechanisms that evolved in response to such challenges, (3) specified four sources of adaptive variability for the sensitivity of each mechanism (i.e., personality traits, sex, age, and ecological conditions), and (4) linked these mechanisms to the story features that trigger them. This comprehensive framework lays the ground for a theory-driven research program for the study of fictional stories, their content, distribution, structure, and cultural evolution

The Cognitive Foundations of Fictional Stories

We hypothesize that fictional storiesare highly successful in human cultures partly because they activateevolved cognitive mechanisms, for instance for finding mates (e.g., in romance fiction), exploring the world (e.g., in adventure and speculative fiction), or avoiding predators (e.g., in horror fiction). In this paper, we put forward a comprehensive framework to study fiction through this evolutionary lens.The primary goal of this framework is to carve fictional storiesat their cognitive jointsusing an evolutionary framework. Reviewinga wide range of adaptive variations in human psychology–in personality and developmental psychology, behavioral ecology, and evolutionary biology, among other disciplines –, this framework also addresses the question ofinterindividual differences in preferences for different features in fictional stories. It generates a wide range of predictions about the patterns ofcombinations of such features, according to the pattenrs of variations in the mechanisms triggered by fictional stories. As a result of a highly collaborative effort, we present a comprehensive review of evolved cognitive mechanisms that fictional stories activate.To generate this review, we (1) listedmore than 70adaptivechallengeshumans faced in the course of their evolution, (2) identifiedthe adaptive psychological mechanisms that evolved in response to such challenges, (3) specifiedfoursources ofadaptive variabilityfor the sensitivity of each mechanism(i.e., personality traits, sex, age, and ecological conditions), and (4) linkedthese mechanismsto the story features that trigger them. This comprehensive framework lays the ground for a theory-driven research program for the study of fictional stories, their content, distribution, structure, andculturalevolution

Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer (PARSPORT): a phase 3 multicentre randomised controlled trial

SummaryBackgroundXerostomia is the most common late side-effect of radiotherapy to the head and neck. Compared with conventional radiotherapy, intensity-modulated radiotherapy (IMRT) can reduce irradiation of the parotid glands. We assessed the hypothesis that parotid-sparing IMRT reduces the incidence of severe xerostomia.MethodsWe undertook a randomised controlled trial between Jan 21, 2003, and Dec 7, 2007, that compared conventional radiotherapy (control) with parotid-sparing IMRT. We randomly assigned patients with histologically confirmed pharyngeal squamous-cell carcinoma (T1–4, N0–3, M0) at six UK radiotherapy centres between the two radiotherapy techniques (1:1 ratio). A dose of 60 or 65 Gy was prescribed in 30 daily fractions given Monday to Friday. Treatment was not masked. Randomisation was by computer-generated permuted blocks and was stratified by centre and tumour site. Our primary endpoint was the proportion of patients with grade 2 or worse xerostomia at 12 months, as assessed by the Late Effects of Normal Tissue (LENT SOMA) scale. Analyses were done on an intention-to-treat basis, with all patients who had assessments included. Long-term follow-up of patients is ongoing. This study is registered with the International Standard Randomised Controlled Trial register, number ISRCTN48243537.Findings47 patients were assigned to each treatment arm. Median follow-up was 44·0 months (IQR 30·0–59·7). Six patients from each group died before 12 months and seven patients from the conventional radiotherapy and two from the IMRT group were not assessed at 12 months. At 12 months xerostomia side-effects were reported in 73 of 82 alive patients; grade 2 or worse xerostomia at 12 months was significantly lower in the IMRT group than in the conventional radiotherapy group (25 [74%; 95% CI 56–87] of 34 patients given conventional radiotherapy vs 15 [38%; 23–55] of 39 given IMRT, p=0·0027). The only recorded acute adverse event of grade 2 or worse that differed significantly between the treatment groups was fatigue, which was more prevalent in the IMRT group (18 [41%; 99% CI 23–61] of 44 patients given conventional radiotherapy vs 35 [74%; 55–89] of 47 given IMRT, p=0·0015). At 24 months, grade 2 or worse xerostomia was significantly less common with IMRT than with conventional radiotherapy (20 [83%; 95% CI 63–95] of 24 patients given conventional radiotherapy vs nine [29%; 14–48] of 31 given IMRT; p<0·0001). At 12 and 24 months, significant benefits were seen in recovery of saliva secretion with IMRT compared with conventional radiotherapy, as were clinically significant improvements in dry-mouth-specific and global quality of life scores. At 24 months, no significant differences were seen between randomised groups in non-xerostomia late toxicities, locoregional control, or overall survival.InterpretationSparing the parotid glands with IMRT significantly reduces the incidence of xerostomia and leads to recovery of saliva secretion and improvements in associated quality of life, and thus strongly supports a role for IMRT in squamous-cell carcinoma of the head and neck.FundingCancer Research UK (CRUK/03/005)