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Trial Results Support 'new Gold Standard' For Head And Neck Cancer Radiotherapy
Phase III trial results on a precision radiotherapy technique support a "new gold standard" for treating head and neck cancer patients. The research suggests the new approach can reduce the risk of swallowing problems after radiotherapy, without impacting the success of treatment.
The Dysphagia-Aspiration Related Structures (DARS) trial compared dysphagia-optimized intensity-modulated radiotherapy (DO-IMRT) with standard IMRT.
Reducing radiation to muscles involved in swallowingDO-IMRT optimizes IMRT to reduce the risk of swallowing difficulties, known as dysphagia. This common side effect of radiotherapy for head and neck cancer can, in some cases, leave patients needing a permanent feeding tube. DO-IMRT lowers the risk of dysphagia by reducing radiation to the pharyngeal muscles, which support swallowing.
The DARS study included 112 newly diagnosed participants with oropharyngeal and hypopharyngeal cancers (tumors of the throat) from centers across the U.K. And Ireland. Half received standard IMRT and half received DO-IMRT for six weeks. Final results from the trial, which were published in The Lancet Oncology, revealed that:
Ian McAllister, 73 from Wandsworth, was diagnosed with oropharyngeal cancer, a type of head and neck cancer, last January. He was treated at The Royal Marsden with dysphagia optimized radiotherapy which has helped him avoid needing a feeding tube. His most recent scan results also showed no evidence of cancer.
Ian said, "I first noticed something was wrong last summer when I woke up with a numb tongue. I thought it was from a hot coffee burn, so I didn't think much of it. However, it progressed to feeling itchy and, by December, I lost my sense of taste down the left side of my tongue.
"Following tests in my local hospital, I was diagnosed with cancer just after Christmas. The disease was significant as the tumor was staged as T4 and had spread to my lymph nodes on both sides, soft palate and was wrapped around my left tonsil.
"I was referred to The Royal Marsden and told that I would need radiotherapy. My team warned me that the treatment could leave me needing a feeding tube, which would have meant being restricted to liquid or pureed food. However, I understand my treatment was tailored to help minimize the risk of this, which is fantastic.
"During the first couple of weeks of radiotherapy, I thought the treatment was a breeze, but the side effects built up. By week four, I had lost my sense of taste and my saliva glands had stopped working, so eating was a real struggle. However, thanks to this optimized radiotherapy and The Royal Marsden's dieticians and speech and language therapists who supported me with diet plans, mouth exercises and buckets of encouragement, I achieved my goal of playing golf three weeks after finishing treatment. I now no longer have trouble swallowing and although my taste and saliva glands have not as yet returned, I am confident my rehab will enable me to achieve that goal."
'A new gold standard'Study lead Professor Chris Nutting, consultant clinical oncologist at The Royal Marsden NHS Foundation Trust and Professor of Radiation Oncology at The Institute of Cancer Research, London, said, "The final results from this study support a new gold standard for treating head and neck cancer patients with radiotherapy. We have demonstrated that this targeted form of radiotherapy can spare the swallowing muscles of patients without impacting the success of their treatment.
"This approach involves oncologists and physicists spending some additional time designing the treatment based on the size and position of the tumor. A computer will then plan the dose and route which turns the radiation into lots of smaller, more precise beams that help to protect the throat where possible. As these tweaks to the treatment can significantly improve quality of life, we hope more centers will implement this practice."
Professor Justin Roe, consultant speech and language therapist and joint head of the Department of Speech, Voice and Swallowing at The Royal Marsden NHS Foundation Trust, said, "The vast majority of patients I support have had a head and neck cancer diagnosis and many unfortunately experience swallowing problems during and following treatment, which often includes radiotherapy. I regularly see people who no longer enjoy food and drink, or feel too embarrassed to consume them around others, which can lead to depression and isolation.
"Dysphagia can also cause other serious medical problems such as malnutrition, dehydration and, in some cases, respiratory complications. It has been a privilege to support this study and I hope to see many more patients benefit from this tailored form of radiotherapy in the future."
'Cutting-edge radiotherapy'Professor Emma Hall, Co-Director of the Clinical Trials and Statistics Unit at The Institute of Cancer Research, London, which coordinated the trial, said, "Maintaining the ability to eat and drink normally following treatment for head and neck cancer is incredibly important for patients' well-being. We're delighted our trial has shown it is possible to tailor how we deliver cutting-edge radiotherapy to minimize damage to key muscles and structures involved in swallowing, and help more people continue to enjoy eating and drinking following therapy.
"This is just one example of how advanced radiotherapy techniques like Do-IMRT can help more patients live well, with fewer side effects, after receiving cancer treatment."
Martin Ledwick, Cancer Research UK's head nurse, said, "Behind the results of each clinical trial, there are real people who deserve the best possible quality of life. It's important the interventions not only work, but can be kinder so they are still able to enjoy life's pleasures.
"It's difficult for many of us to imagine not being able to swallow properly, but this can be the reality for head and neck cancer patients post-treatment.
"These promising results could make life after treatment brighter for head and neck cancer patients, and we look forward to seeing this kinder form of radiotherapy make its way to the clinic."
More information: Christopher Nutting et al, Dysphagia-optimised intensity-modulated radiotherapy versus standard intensity-modulated radiotherapy in patients with head and neck cancer (DARS): a phase 3, multicentre, randomised, controlled trial, The Lancet Oncology (2023). DOI: 10.1016/S1470-2045(23)00265-6
Citation: Trial results support 'new gold standard' for head and neck cancer radiotherapy (2023, November 24) retrieved 25 November 2023 from https://medicalxpress.Com/news/2023-11-trial-results-gold-standard-neck.Html
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'Breakthrough' CRISPR Treatment Slashes Cholesterol In First Human Clinical Trial
CRISPR-based therapies just hit another milestone.
In a small clinical trial with 10 people genetically prone to dangerously high levels of cholesterol, a single infusion of the precision gene editor slashed the artery-clogging fat by up to 55 percent. If all goes well, the one-shot treatment could last a lifetime.
The trial, led by Verve Therapeutics, is the first to explore CRISPR for a chronic disease that's usually managed with decades of daily pills. It also marks the first use of a newer class of gene editors directly in humans. Called base editing, the technology is more precise—and potentially safer—than the original set of CRISPR tools. The new treatment, VERVE-101, uses a base editor to disable a gene encoding a liver protein that regulates cholesterol.
To be clear, these results are just a sneak peek into the trial, which was designed to test for safety, rather than the treatment's efficacy. Not all participants responded well. Two people suffered severe heart issues, with one case potentially related to the treatment.
Nevertheless, "it is a breakthrough to have shown in humans that in vivo [in the body] base editing works efficiently in the liver," Dr. Gerald Schwank at the University of Zurich, who wasn't involved in the trial, told Science.
Give Your Heart a BreakCRISPR has worked wonders for previously untreatable cancers. Last week, it was also approved in the United Kingdom for the blood diseases sickle cell and beta thalassemia.
For these treatments, scientists extract immune cells or blood cells from the body, edit the cells using CRISPR to correct the genetic mistake, and reinfuse the treated cells into the patient. For edited cells to "take," patients must undergo a grueling treatment to wipe out existing diseased cells in the bone marrow and open space for the edited replacements.
Verve is taking a different approach: Instead of isolating cells for gene editing, the tools are infused into the bloodstream where they edit genes directly inside the body. It's a big gamble. Most of our cells contain the same DNA. Once injected, the tools could go on a rampage and edit the targeted gene throughout the body, causing dangerous side effects.
Verve tackled this concern head on by pairing base editing with nanoparticles.
The trial targeted PCSK9, a liver protein that keeps low-density lipoprotein (LDL), or "bad cholesterol," levels at bay. In familial hypercholesterolemia, a single mutated letter in PCSK9 alters its function, causing LDL levels to grow dangerously. People with this inherited disorder are at risk of life-threatening heart problems by the age of 50 and need to take statin drugs to keep their cholesterol in check. But the lifelong regime is tough to maintain.
A Targeted CRISPR TorpedoVerve designed a "one-and-done" treatment to correct the PCSK9 mutation in these patients.
The therapy employs two key strategies to boost efficacy.
The first is called base editing. The original CRISPR toolset acts like scissors, cutting both strands of DNA, making the edit, and patching the ends back together. The process often leaves room for mistakes, such as the unintended rearranging of sequences that could turn on cancer genes, leading some experts to call it "genetic vandalism." Base editing, in contrast, is far more precise. Like a scalpel, base editors only nick one DNA strand, and are therefore far less likely to injure non-targeted parts of the genome.
Verve's treatment encodes the base editor in two different RNA molecules. One instructs the cells to make the components of the gene editing tool—similar to how Covid-19 vaccines work. The other strand of RNA guides the tool to PCSK9. Once edited, the treated gene produces a shortened, non-functional version of the faulty protein responsible for the condition.
The delivery method also boosts efficacy. Base editing components can be encoded into harmless viruses or wrapped inside fatty nanoparticles for delivery. Verve took the second approach because these nanoparticles are often first shuttled into the liver—exactly where the treatment should go—and are less likely to cause an immune reaction than viruses.
There's just one problem. Base editing has never been used to edit genes in the body before.
A non-human trial in 2021 showed the idea could work. In macaque monkeys, a single shot of the editor into the bloodstream reduced the gene's function in the liver, causing LDL levels to drop 60 percent. The treatment lasted at least eight months with barely any side effects.
Safety FirstThe new trial built on previous results to assess the treatment's safety in 10 patients with familial hypercholesterolemia. One patient dropped out before completing the trial.
The team was careful. To detect potential side effects, six patients were treated with a small dose unlikely to reverse the disorder.
Three patients received a higher dose of the base editor and saw dramatic effects. PCSK9 protein levels in their livers dropped between 47 and 84 percent. Circulating LDL fell to about half its prior levels—an effect that lasted at least six months. Follow-ups are ongoing.
The efficacy of the higher dose came at a price. At lower doses, the treatment was well tolerated overall with minimal side effects. But at higher doses, it seemed to temporarily tax the liver, bumping up markers for liver stress that gradually subsided.
More troubling were two severe events in patients with advanced heart blockage. One person receiving a low dose died from cardiac arrest about five weeks after the treatment. According to a review board, the death was likely due to underlying conditions, not the treatment.
Another patient infused with a higher dose suffered a heart attack a day after treatment, suggesting the episode could have been related. However, he had intermittent chest pains before the infusion that hadn't been disclosed to the team. His symptoms would have excluded him from the trial.
A Promising PathOverall, an independent board monitoring data and safety determined the treatment safe. Still, there are plenty of unknowns. Like other gene editing tools, base editing poses the risk of off-target snips—something this trial did not specifically examine. Long-term safety and efficacy of the treatment are also unknown.
But the team is encouraged by these early results. "We are excited to have reached this milestone of positive first-in-human data supporting the significant potential for in vivo liver gene editing as a treatment for patients with [familial hypercholesterolemia]," said Dr. Sekar Kathiresan, CEO and cofounder of Verve.
The trial was conducted in the United Kingdom and New Zealand. Recently, US regulators approved the therapy for testing. They plan to enroll roughly 40 more patients.
Meanwhile, a new version of the therapy, VERVE-102, is already in the works. The newcomer uses a similar base editing technology and an upgraded nanoparticle carrier with potentially better targeting.
If all goes well, the team will launch a randomized, placebo-controlled trial by 2025. So far, the company hasn't released a price tag for the therapy. But the cost of existing gene therapies can run into the millions of dollars.
To Kathiresan, treatments like this one could benefit more than patients with familial hypercholesterolemia. High cholesterol is a leading health problem. A dose of the base editor in middle age could potentially nip cholesterol buildup in the bud—and in turn, lower risk of heart disease and death.
"That's the ultimate vision," he said.
Image Credit: Scientific Animations / Wikimedia Commons
Clinical Trial Results Give New Hope For Children With Rare Gliomas
A collaboration of researchers, led by UCL and Great Ormond Street Hospital, have published successful results from a Phase II clinical trial for the treatment of BRAF mutated low-grade paediatric gliomas.
Gliomas are cancerous brain tumours that start in glial cells – the supporting cells of the brain.
The results from the TADPOLE-G study, published in the New England Journal of Medicine and the Journal of Clinical Oncology, are the first to demonstrate a clear clinical benefit of combining the therapies of Dabrafenib and Trametinib (Novartis) in BRAF mutated low- and high-grade paediatric gliomas respectively.
For children with paediatric low-grade gliomas, the normal course of treatment is a full surgical removal. However, for children where this is not possible, additional treatments like chemotherapy are required. These patients often experience multiple relapses, further disease progression and serious side effects.
In the randomised trial, 73 children with BRAF mutated low-grade gliomas (BM-LGG) were treated with Dabrafenib and Trametinib. Their outcomes were compared to 37 patients who were treated with standard chemotherapy drugs.
Researchers found that the combination therapy lessened chemotherapy side effects, it also improved overall response rate by over four-fold and increased median progression free survival from 7.4 months with chemotherapy to 20.1 months with the new treatment.
The new research follows on from the publication of results from the same study in patients with BRAF mutated high-grade gliomas (BM-HGG)*.
Children with high-grade gliomas often undergo full surgical resections, followed by radiotherapy and chemotherapy. Unfortunately, overall, less than one in five children respond well to treatment and two-year survival is less than 35%, with many patients' cancer returning.
41 children who had previously received treatment for their BM-HGG took part in the second study. The treatment led to 56% of patients responding to treatment overall - a significant improvement compared to previous chemotherapy trials - and a median duration of response of 22.2 months.
The study leaders say that these trials demonstrate a clear clinical benefit of the dual treatment, with the recommendation being that it become a first-line treatment for BM-LGG and a clinical option for those with relapsed/refractory BM-HGG.
Evidence from these trials is now being used as part of a NICE scoping review** to appraise the clinical and cost effectiveness of the treatments. The US Food and Drug Administration have already approved the treatment*** for children with low-grade glioma.
Professor Darren Hargrave (UCL Great Ormond Street Institute of Child Health and GOSH), said: "The results of these studies highlight how targeted drug therapies can offer patients new treatment avenues that not only improve outcomes but reduce the side effects often associated with cancer therapies."
Mutations in the BRAF gene were first identified as drivers of cancer in the early 2000s and now targeted therapies such as Dabrafenib and Trametinib are being used to treat melanoma and non-small cell lung cancer in patients with mutations in the BRAF gene.
The BRAF mutation is present in around 15-20% of paediatric low-grade gliomas and around 5-10% of high-grade gliomas in children. These studies are the first to investigate the effectiveness of the combination therapy in paediatric gliomas.
Professor Hargrave chaired the TADPOLE-G Clinical Trial Steering group and led recruitment at GOSH for both this trial and the earlier Phase I arm of the trial.
He said: "It has been incredible to watch research move our ability to treat specific cancers forward at such a rapid pace. I was involved in the original study that identified BRAF gene mutations as drivers of cancer and so it has been fantastic to now be able to see treatments that target the mutation in clinical trials for paediatric gliomas.
"These studies demonstrate the power of collaborative, global research to find new treatments for rare cancers. We'd like to thank all the patients and families who make research like this possible."
Paediatric gliomas, although the most common type of brain tumour, are still rare, especially when divided into specific molecular subtypes such as BRAF mutated tumours. Global collaboration is therefore essential to achieve timely and scientifically significant results, which led the TADPOLE-G study to enrol patients from 58 sites in 20 countries.
Gerrit Zijlstra, Chief Medical Officer, Novartis UK, said: "New treatments that help improve outcomes and reduce side effects for young patients living with BRAF V600 low- and high-grade gliomas address unmet patient need, where treatment options are very limited.
"We welcome the results of the TADPOLE-G clinical trial and are humbled to be a part of an international scientific community effort in developing targeted therapies based on the unique genetic features of a patient's tumour."
* https://ascopubs.Org/doi/full/10.1200/JCO.23.00558
** https://www.Nice.Org.Uk/guidance/indevelopment/gid-ta11006
*** https://www.Fda.Gov/drugs/resources-information-approved-drugs/fda-approves-dabrafenib-trametinib-pediatric-patients-low-grade-glioma-braf-v600e-mutation
JournalNew England Journal of Medicine
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