Champiat and colleagues suggest that a small subset of patients at their center treated with PD1/PDL1 inhibitors appear to exhibit hyperprogression of disease. This commentary goes over some ...limitations in their preliminary analysis, a possible mechanism to explain the phenomenon, and a means by which other investigators can attempt to validate and further characterize these results.
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A real‐world data (RWD) analysis revealed potentially worse outcomes for diabetic patients with lung cancer receiving immunotherapy. The effort emphasizes the need to bridge RWD and randomized ...clinical trials to enhance understanding of how comorbid conditions affect overall patient health.
Abstract
We consider the design of phase II trials evaluating combinations of experimental therapies. In the modern era, many immunotherapy and targeted therapy regimens are being developed as ...combination regimens, including combinations consisting only of experimental agents. In some clinical or drug development scenarios, it may be difficult to isolate the effect of the individual agents composing a combination of this type, which makes the evaluation of the combination challenging. One such scenario arises when none of the agents making up the experimental combination have demonstrated single-agent activity in the clinical setting of interest. One solution to this problem is to use a randomized comparative trial in which the combination of interest is compared with 1 or both of its component agents, but some modifications to more traditional randomized comparative phase II trials must be made because all arms in such a trial would be experimental. In this manuscript, we present sensible modifications to randomized phase II trial designs that can be used in 2 common drug development scenarios of this type and provide a detailed discussion of the practical aspects of designing these trials. We also include 2 worked examples to further illustrate how to design such a trial.
Purpose
Oral mucositis is a major complication of anticancer therapy yet the literature focuses on immediate (acute) mucosal changes and hardly describes the chronic form. We aim to report the ...clinical manifestations of
chronic mucositis
.
Methods
A retrospective chart review of oral mucositis referrals was performed. Inclusion/exclusion criteria defined the patients that were considered to have chronic mucositis.
Results
Four female patients treated for tongue/lower lip squamous cell carcinoma were included. Extensive painful oral mucositis lesions developed in all patients during the course of radiotherapy, with ulcers remaining for 5–24 months after completion of therapy. We describe two presentations, namely the
persistent form
(long-lasting ulcers continuing from acute ulcers) and the
recurrent form
(new discrete ulcers appearing on atrophic mucosa following the completion of radiotherapy).
Conclusions
The long-term oral complications of radiotherapy to the head and neck may include chronic atrophic, erythematous, and/or ulcerated lesions. A diagnosis of
chronic oral mucositis
should be considered when the lesions are observed at least 3 months after radiotherapy, and other possible etiologies have been excluded. The influence of age and comorbidities (primarily diabetes mellitus) on chronic mucositis, the significance to patient’s quality of life, and the management of chronic mucositis are important subjects for future research.
Over the next decade, more than a million eukaryotic species are expected to be fully sequenced. This has the potential to improve our understanding of genotype and phenotype crosstalk, gene function ...and interactions, and answer evolutionary questions. Here, we develop a machine-learning approach for utilizing phylogenetic profiles across 1154 eukaryotic species. This method integrates co-evolution across eukaryotic clades to predict functional interactions between human genes and the context for these interactions. We benchmark our approach showing a 14% performance increase (auROC) compared to previous methods. Using this approach, we predict functional annotations for less studied genes. We focus on DNA repair and verify that 9 of the top 50 predicted genes have been identified elsewhere, with others previously prioritized by high-throughput screens. Overall, our approach enables better annotation of function and functional interactions and facilitates the understanding of evolutionary processes underlying co-evolution. The manuscript is accompanied by a webserver available at: https://mlpp.cs.huji.ac.il .
Background
Mucositis is a significant toxicity of cancer therapy with numerous systemic sequelae. The goal of this systematic review was to update the Multinational Association of Supportive Care in ...Cancer and International Society of Oral Oncology (MASCC/ISOO) Clinical Practice Guidelines for the management of mucositis.
Methods
The literature was reviewed systematically to identify interventions for mucositis. Studies were rated according to the presence of major and minor flaws according to previously published criteria. The body of evidence for each intervention and in each treatment setting was assigned a level of evidence based on previously published criteria. Guidelines were developed based on the level of evidence, with 3 possible guideline determinations: recommendation, suggestion, or no guideline possible.
Results
The guideline covers evidence from 1197 publications related to oral or gastrointestinal mucositis. Thirteen new guidelines were developed for or against the use of various interventions in specific treatment settings, and 11 previous guidelines were confirmed after aa review of new evidence. Thirteen previously established guidelines were carried over because there was no new evidence for these interventions.
Conclusions
The updated MASCC/ISOO Clinical Practice Guidelines for mucositis provide professional health caregivers with a clinical setting‐specific, evidence‐based tool to help with the management of mucositis in patients who have cancer.
The Multinational Association of Supportive Care in Cancer and the International Society of Oral Oncology developed clinical practice guidelines for the management of mucositis, with the first edition published in 2004 and periodically updated. This summary presents the 2019/2020 guidelines update, which is based on a systematic review, and generates a tool that will help clinicians to select evidence‐based interventions.
Merkel-cell carcinoma is an aggressive skin cancer that is linked to exposure to ultraviolet light and the Merkel-cell polyomavirus (MCPyV). Advanced Merkel-cell carcinoma often responds to ...chemotherapy, but responses are transient. Blocking the programmed death 1 (PD-1) immune inhibitory pathway is of interest, because these tumors often express PD-L1, and MCPyV-specific T cells express PD-1.
In this multicenter, phase 2, noncontrolled study, we assigned adults with advanced Merkel-cell carcinoma who had received no previous systemic therapy to receive pembrolizumab (anti-PD-1) at a dose of 2 mg per kilogram of body weight every 3 weeks. The primary end point was the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1. Efficacy was correlated with tumor viral status, as assessed by serologic and immunohistochemical testing.
A total of 26 patients received at least one dose of pembrolizumab. The objective response rate among the 25 patients with at least one evaluation during treatment was 56% (95% confidence interval CI, 35 to 76); 4 patients had a complete response, and 10 had a partial response. With a median follow-up of 33 weeks (range, 7 to 53), relapses occurred in 2 of the 14 patients who had had a response (14%). The response duration ranged from at least 2.2 months to at least 9.7 months. The rate of progression-free survival at 6 months was 67% (95% CI, 49 to 86). A total of 17 of the 26 patients (65%) had virus-positive tumors. The response rate was 62% among patients with MCPyV-positive tumors (10 of 16 patients) and 44% among those with virus-negative tumors (4 of 9 patients). Drug-related grade 3 or 4 adverse events occurred in 15% of the patients.
In this study, first-line therapy with pembrolizumab in patients with advanced Merkel-cell carcinoma was associated with an objective response rate of 56%. Responses were observed in patients with virus-positive tumors and those with virus-negative tumors. (Funded by the National Cancer Institute and Merck; ClinicalTrials.gov number, NCT02267603.).
Purpose
To systematically review the literature and update the evidence-based clinical practice guidelines for the use of photobiomodulation (PBM), such as laser and other light therapies, for the ...prevention and/or treatment of oral mucositis (OM).
Methods
A systematic review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society for Oral Oncology (MASCC/ISOO) using PubMed and Web of Science. We followed the MASCC methods for systematic review and guidelines development. The rigorously evaluated evidence for each intervention, in each cancer treatment setting, was assigned a level-of-evidence (LoE). Based on the LoE, one of the following guidelines was determined: Recommendation, Suggestion, or No Guideline Possible.
Results
Recommendations are made for the prevention of OM and related pain with PBM therapy in cancer patients treated with one of the following modalities: hematopoietic stem cell transplantation, head and neck (H&N) radiotherapy (without chemotherapy), and H&N radiotherapy with chemotherapy. For each of these modalities, we recommend 1–2 clinically effective protocols; the clinician should adhere to all parameters of the protocol selected. Due to inadequate evidence, currently, No Guideline Possible for treatment of established OM or for management of chemotherapy-related OM. The reported clinical settings were extremely variable, limiting data integration.
Conclusions
The evidence supports the use of specific settings of PBM therapy for the prevention of OM in specific patient populations. Under these circumstances, PBM is recommended for the prevention of OM. The guidelines are subject to continuous update based on new published data.
Patients with non-small-cell lung cancer (NSCLC) that is resistant to PD-1 and PD-L1 (PDL-1)-targeted therapy have poor outcomes. Studies suggest that radiotherapy could enhance antitumour immunity. ...Therefore, we investigated the potential benefit of PD-L1 (durvalumab) and CTLA-4 (tremelimumab) inhibition alone or combined with radiotherapy.
This open-label, multicentre, randomised, phase 2 trial was done by the National Cancer Institute Experimental Therapeutics Clinical Trials Network at 18 US sites. Patients aged 18 years or older with metastatic NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, and progression during previous PD(L)-1 therapy were eligible. They were randomly assigned (1:1:1) in a web-based system by the study statistician using a permuted block scheme (block sizes of three or six) without stratification to receive either durvalumab (1500 mg intravenously every 4 weeks for a maximum of 13 cycles) plus tremelimumab (75 mg intravenously every 4 weeks for a maximum of four cycles) alone or with low-dose (0·5 Gy delivered twice per day, repeated for 2 days during each of the first four cycles of therapy) or hypofractionated radiotherapy (24 Gy total delivered over three 8-Gy fractions during the first cycle only), 1 week after initial durvalumab–tremelimumab administration. Study treatment was continued until 1 year or until progression. The primary endpoint was overall response rate (best locally assessed confirmed response of a partial or complete response) and, along with safety, was analysed in patients who received at least one dose of study therapy. The trial is registered with ClinicalTrials.gov, NCT02888743, and is now complete.
Between Aug 24, 2017, and March 29, 2019, 90 patients were enrolled and randomly assigned, of whom 78 (26 per group) were treated. This trial was stopped due to futility assessed in an interim analysis. At a median follow-up of 12·4 months (IQR 7·8–15·1), there were no differences in overall response rates between the durvalumab–tremelimumab alone group (three 11·5%, 90% CI 1·2–21·8 of 26 patients) and the low-dose radiotherapy group (two 7·7%, 0·0–16·3 of 26 patients; p=0·64) or the hypofractionated radiotherapy group (three 11·5%, 1·2–21·8 of 26 patients; p=0·99). The most common grade 3–4 adverse events were dyspnoea (two 8% in the durvalumab–tremelimumab alone group; three 12% in the low-dose radiotherapy group; and three 12% in the hypofractionated radiotherapy group) and hyponatraemia (one 4% in the durvalumab–tremelimumab alone group vs two 8% in the low-dose radiotherapy group vs three 12% in the hypofractionated radiotherapy group). Treatment-related serious adverse events occurred in one (4%) patient in the durvalumab–tremelimumab alone group (maculopapular rash), five (19%) patients in the low-dose radiotherapy group (abdominal pain, diarrhoea, dyspnoea, hypokalemia, and respiratory failure), and four (15%) patients in the hypofractionated group (adrenal insufficiency, colitis, diarrhoea, and hyponatremia). In the low-dose radiotherapy group, there was one death from respiratory failure potentially related to study therapy.
Radiotherapy did not increase responses to combined PD-L1 plus CTLA-4 inhibition in patients with NSCLC resistant to PD(L)-1 therapy. However, PD-L1 plus CTLA-4 therapy could be a treatment option for some patients. Future studies should refine predictive biomarkers in this setting.
The US National Institutes of Health and the Dana-Farber Cancer Institute.
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