SummaryBackgroundThe incidence of human papillomavirus (HPV)-positive oropharyngeal cancer, a disease affecting younger patients, is rapidly increasing. Cetuximab, an epidermal growth factor receptor inhibitor, has been proposed for treatment de-escalation in this setting to reduce the toxicity of standard cisplatin treatment, but no randomised evidence exists for the efficacy of this strategy.MethodsWe did an open-label randomised controlled phase 3 trial at 32 head and neck treatment centres in Ireland, the Netherlands, and the UK, in patients aged 18 years or older with HPV-positive low-risk oropharyngeal cancer (non-smokers or lifetime smokers with a smoking history of <10 pack-years). Eligible patients were randomly assigned (1:1) to receive, in addition to radiotherapy (70 Gy in 35 fractions), either intravenous cisplatin (100 mg/m2 on days 1, 22, and 43 of radiotherapy) or intravenous cetuximab (400 mg/m2 loading dose followed by seven weekly infusions of 250 mg/m2). The primary outcome was overall severe (grade 3–5) toxicity events at 24 months from the end of treatment. The primary outcome was assessed by intention-to-treat and per-protocol analyses. This trial is registered with the ISRCTN registry, number ISRCTN33522080.FindingsBetween Nov 12, 2012, and Oct 1, 2016, 334 patients were recruited (166 in the cisplatin group and 168 in the cetuximab group). Overall (acute and late) severe (grade 3–5) toxicity did not differ significantly between treatment groups at 24 months (mean number of events per patient 4·8 [95% CI 4·2–5·4] with cisplatin vs 4·8 [4·2–5·4] with cetuximab; p=0·98). At 24 months, overall all-grade toxicity did not differ significantly either (mean number of events per patient 29·2 [95% CI 27·3–31·0] with cisplatin vs 30·1 [28·3–31·9] with cetuximab; p=0·49). However, there was a significant difference between cisplatin and cetuximab in 2-year overall survival (97·5% vs 89·4%, hazard ratio 5·0 [95% CI 1·7–14·7]; p=0·001) and 2-year recurrence (6·0% vs 16·1%, 3·4 [1·6–7·2]; p=0·0007).InterpretationCompared with the standard cisplatin regimen, cetuximab showed no benefit in terms of reduced toxicity, but instead showed significant detriment in terms of tumour control. Cisplatin and radiotherapy should be used as the standard of care for HPV-positive low-risk patients who are able to tolerate cisplatin.FundingCancer Research UK.
BackgroundThe application of adaptive design methodology within a clinical trial setting is becoming increasingly popular. However the application of these methods within trials is not being reported as adaptive designs hence making it more difficult to capture the emerging use of these designs. Within this review, we aim to understand how adaptive design methodology is being reported, whether these methods are explicitly stated as an ‘adaptive design’ or if it has to be inferred and to identify whether these methods are applied prospectively or concurrently.MethodsThree databases; Embase, Ovid and PubMed were chosen to conduct the literature search. The inclusion criteria for the review were phase II, phase III and phase II/III randomised controlled trials within the field of Oncology that published trial results in 2015. A variety of search terms related to adaptive designs were used.ResultsA total of 734 results were identified, after screening 54 were eligible. Adaptive designs were more commonly applied in phase III confirmatory trials. The majority of the papers performed an interim analysis, which included some sort of stopping criteria. Additionally only two papers explicitly stated the term ‘adaptive design’ and therefore for most of the papers, it had to be inferred that adaptive methods was applied. Sixty-five applications of adaptive design methods were applied, from which the most common method was an adaptation using group sequential methods.ConclusionsThis review indicated that the reporting of adaptive design methodology within clinical trials needs improving. The proposed extension to the current CONSORT 2010 guidelines could help capture adaptive design methods. Furthermore provide an essential aid to those involved with clinical trials.Electronic supplementary materialThe online version of this article (doi:10.1186/s12874-017-0393-6) contains supplementary material, which is available to authorized users.
B-cell maturation antigen (BCMA)-targeting therapies, including bispecific antibodies (BsAbs) and antibody-drug conjugates (ADC), are promising treatments for multiple myeloma (MM), but disease may progress after their use. CARTITUDE-2 is a phase 2, multicohort study evaluating the safety and efficacy of cilta-cel, an anti-BCMA chimeric antigen receptor T therapy, in various myeloma patient populations. Patients in cohort C progressed despite treatment with a proteasome inhibitor, immunomodulatory drug, anti-CD38 antibody, and non‑cellular anti-BCMA immunotherapy. A single cilta-cel infusion was given after lymphodepletion. The primary end point was minimal residual disease (MRD) negativity at 10−5. Overall, 20 patients were treated (13 ADC-exposed; 7 BsAb-exposed; 1 in the ADC group also had prior BsAb exposure); 16 (80%) were refractory to prior anti-BCMA therapy. At a median follow-up of 11.3 months (range, 0.6-16.0), 7/20 (35%) patients were MRD-negative (7/10 [70.0%] in the MRD-evaluable subset). Overall response rate (95% CI) was 60.0% (36.1-80.9). Median duration of response and progression-free survival (95% CI) were 11.5 (7.9-not estimable) and 9.1 (1.5-not estimable) months, respectively. The most common adverse events were hematologic. Cytokine release syndrome occurred in 12 (60%) patients (all grade 1/2); 4 had immune effector cell-associated neurotoxicity syndrome (2 grade 3/4); none had parkinsonism. Seven (35%) patients died (3 of progressive disease, 4 of adverse events [1 treatment-related, 3 unrelated]). Cilta-cel induced favorable responses in patients with relapsed/refractory MM and prior exposure to anti-BCMA treatment who have exhausted other therapies. This trial was registered at www.clinicaltrials.gov as #NCT04133636.
Background: PRMT5 regulates proteins important for tumorigenesis via symmetric arginine dimethylation (SDMA). JNJ64619178 is an oral, potent and selective PRMT5 inhibitor that demonstrates efficacy in multiple tumor models. Here, we present a phase I study of JNJ64619178 in adults with advanced solid tumors and non-Hodgkin lymphoma (Part 1).Methods: Dose escalation was supported by a modified continual reassessment method. Patients (pts) received JNJ64619178 either intermittently (14 days on/7 days off) or once daily (QD) on a 21-day cycle. Safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy were evaluated to identify the recommended phase II doses (RP2D).Results: Fifty-four pts were enrolled as of 17 Mar 2020. The most common tumor types were adenoid cystic carcinoma (ACC; 20%), prostate cancer (15%), and uveal melanoma (13%). Median age was 59 (range 28-82), and median number of prior systemic therapies was 3 (range 0-11). Dosing ranged from 0.5 mg to 4 mg intermittently, and from 1 mg to 2 mg QD. Median treatment duration was 1.5 mo (range 0.4-22.4). The only dose-limiting toxicity observed was thrombocytopenia, at 3 and 4 mg intermittently and 2 mg QD. Fifty-one pts (91%) experienced treatment-related adverse events (TRAE), the most common being thrombocytopenia (52%), anemia (41%), nausea (39%), fatigue (32%), dysgeusia (30%), asthenia (24%), and diarrhea (20%). Grade 3/4 TRAEs in >1 pt were thrombocytopenia (20%), anemia (17%), and neutropenia (6%). Thirty pts (56%) had dose interruptions or reductions due to AE. JNJ64619178 plasma C max and AUC were linearly dose-proportional. Robust target engagement, as measured by plasma SDMA, was achieved even with intermittent dosing. A confirmed partial response (RECIST) was observed in ACC, and 7 pts (13%) with ACC, prostate cancer, salivary gland carcinomas, and other tumor types had stable disease >6 mo. Two provisional RP2Ds were selected: 1.5 mg intermittently and 1 mg QD.Conclusions: JNJ64619178 demonstrated manageable toxicity and preliminary evidence of antitumor activity at selected dose levels. Intermittent dosing maintains target inhibition. Assessment of two provisional RP2Ds is ongoing.Clinical trial identification: NCT03573310.
This study shows a lack of coherence in the management of HFNS in breast cancer survivors, which may lead to reduced adherence to adjuvant therapy. There is an urgent need to develop guidelines to support management of HFNS after breast cancer.
Objective To evaluate whether a structured exercise programme improved functional and health related quality of life outcomes compared with usual care for women at high risk of upper limb disability after breast cancer surgery. Design Multicentre, pragmatic, superiority, randomised controlled trial with economic evaluation. Setting 17 UK National Health Service cancer centres. Participants 392 women undergoing breast cancer surgery, at risk of postoperative upper limb morbidity, randomised (1:1) to usual care with structured exercise (n=196) or usual care alone (n=196). Interventions Usual care (information leaflets) only or usual care plus a physiotherapy led exercise programme, incorporating stretching, strengthening, physical activity, and behavioural change techniques to support adherence to exercise, introduced at 7-10 days postoperatively, with two further appointments at one and three months. Main outcome measures Disability of Arm, Hand and Shoulder (DASH) questionnaire at 12 months, analysed by intention to treat. Secondary outcomes included DASH subscales, pain, complications, health related quality of life, and resource use, from a health and personal social services perspective. Results Between 26 January 2016 and 31 July 2017, 951 patients were screened and 392 (mean age 58.1 years) were randomly allocated, with 382 (97%) eligible for intention to treat analysis. 181 (95%) of 191 participants allocated to exercise attended at least one appointment. Upper limb function improved after exercise compared with usual care (mean DASH 16.3 (SD 17.6) for exercise (n=132); 23.7 (22.9) usual care (n=138); adjusted mean difference 7.81, 95% confidence interval 3.17 to 12.44; P=0.001). Secondary outcomes favoured exercise over usual care, with lower pain intensity at 12 months (adjusted mean difference on numerical rating scale −0.68, −1.23 to −0.12; P=0.02) and fewer arm disability symptoms at 12 months (adjusted mean difference on Functional Assessment of Cancer Therapy-Breast+4 (FACT-B+4) −2.02, −3.11 to −0.93; P=0.001). No increase in complications, lymphoedema, or adverse events was noted in participants allocated to exercise. Exercise accrued lower costs per patient (on average −£387 (€457; $533) (95% confidence interval −£2491 to £1718; 2015 pricing) and was cost effective compared with usual care. Conclusions The PROSPER exercise programme was clinically effective and cost effective and reduced upper limb disability one year after breast cancer treatment in patients at risk of treatment related postoperative complications. Trial registration ISRCTN Registry ISRCTN35358984 .
Background This study aims to develop and validate a new classification system that better predicts combined risk of neurological and neurovascular complications following CBT surgery, crucial for treatment decision‐making. Methods Multinational retrospective cohort study with 199 consecutive cases. A cohort of 132 CBT cases was used to develop the new classification. To undertake external validation, assessment was made between the actual complication rate and predicted risk by the model on an independent cohort (n = 67). Results Univariate analyses showed statistically significant associations between developing a complication and the following factors: craniocaudal dimension, volume, Shamblin classification, and Mehanna types. In the multivariate prognostic model, only Mehanna type remained as a significant risk predictor. The risk of developing complications increases with increasing Mehanna type. Conclusions We have developed and then validated a new classification and risk stratification system for CBTs, which demonstrated better prognostic power for the risk of developing neurovascular complications after surgery.
Background: The De-ESCALaTE HPV trial confirmed the dominance of cisplatin over cetuximab for tumour control in patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC). Here, we present the analysis of healthrelated quality of life (HRQoL), resource use, and health care costs in the trial, as well as complete 2-year survival and recurrence. Materials and methods: Resource use and HRQoL data were collected at intervals from the baseline to 24 months post treatment (PT). Health care costs were estimated using UKbased unit costs. Missing data were imputed. Differences in mean EQ-5D-5L utility index and adjusted cumulative quality-adjusted life years (QALYs) were compared using the Wilcoxon signed-rank test and linear regression, respectively. Mean resource usage and costs were compared through two-sample t-tests. Results: 334 patients were randomised to cisplatin (n Z 166) or cetuximab (n Z 168).At 24 months PT, mean difference was 0$107 QALYs in favour of cisplatin (95% CI: 0$186 to 0$029, p Z 0$007) driven by the mortality difference. Health care costs were similar across all categories except the procurement cost and delivery of the systemic agent, with cetuximab significantly more expensive than cisplatin (£7779 [P < 0.001]). Consequently, total costs at 24 months PT averaged £13517 (SE: £345) per patient for cisplatin and £21064 (SE: £400) for cetuximab (mean difference £7547 [95% CI: £6512 to £8582]). Conclusions: Cisplatin chemoradiotherapy provided more QALYs and was less costly than cetuximab bioradiotherapy, remaining standard of care for nonsurgical treatment of HPVpositive OPSCC.
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