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In a meeting of the Oncologic Drugs Advisory Committee (ODAC), the committee of 11 members unanimously voted that the potential benefits of ciltacabtagene autoleucel (cilta-cel) outweigh its risks for its proposed indication.1
The US Food and Drug Administration (FDA) convened the meeting on March 15, 2024, to obtain committee input on the results of the CARTITUDE-4 trial (ClinicalTrials.gov Identifier: NCT04181827).
The trial data served as the primary evidence for a supplemental Biologics Licensing Application submitted by Janssen Biotech, Inc. for CARVYKTI (cilta-cel) for the treatment of relapsed or refractory multiple myeloma (MM) in adults who have received at least 1 line of therapy and are refractory to lenalidomide.2 Participants who had received 1 to 3 prior lines of therapy for MM were randomly assigned to receive cilta-cel or standard care.
Unmet Need
Based on data from the phase 1b/2 study CARTITUDE-1 (ClinicalTrials.gov Identifier: NCT03548207), cilta-cel is currently approved in the United States for the treatment of relapsed or refractory MM in adults who have received 4 or more prior lines of therapy.3
In the presentation from Janssen Biotech, Inc., Irene Ghobrial, MD, professor of medicine at Dana-Farber Cancer Institute and Harvard Medical School, outlined the current unmet need for the use of CAR-T therapy as early treatment in MM.
Dr Ghobrial cited data showing that 85% of multiple myeloma patients were unable to receive treatments beyond the third line of therapy. This underscores the need for administering effective treatments earlier in the disease course. “Initial treatment is the best chance for deep and durable remissions,” she said.
Additionally, T-cells become exhausted with disease progression. Administering CAR-T therapy earlier in the disease course, when T-cells are less exhausted, is associated with better long-term outcomes, Dr Ghobrial noted.
The current standard care for MM patients is continuous treatment, which contributes to “added toxicity and added burden for the patient,” said Dr Ghobrial. A one-and-done treatment such as cilta-cel early in the disease course creates the opportunity for patients to achieve remission without having to undergo continuous, burdensome treatments.
Trial Data
Jordan Schecter, MD, vice president of research and development for the Janssen Pharmaceutical Companies of Johnson & Johnson, presented data from CARTITUDE-4 at the meeting.1
Cilta-cel was associated with significant and meaningful PFS improvement compared to the standard care arm, and this finding was consistent across subgroups. Median PFS was not reached in the cilta-arm, while it was 11.8 months for the standard care arm.
Additionally, 85% of patients in the cilta-cel arm obtained a response, compared with 67% patients in the standard care arm.
Dr Schecter addressed an increased risk for early death in the cilta-cel arm. “The only period in which we see more deaths in the experimental arm versus standard of care arm is between 0 and 3 months,” he stated. Before 3 months, there were 7 deaths in the cilta-arm and 1 death in the standard care arm.
Dr Schecter noted that a cause for the disparity in early deaths prior to receiving treatment was disease progression in the cilta-cel arm, and not cilta-cel toxicity. For example, 6 out of the 7 deaths prior to 3 months were in patients randomized to cilta-cel, but who progressed prior to infusion with cilta-cel. Additionally, he noted that between 3 and 6 months, the OS curves began to balance and then trended towards fewer deaths in the cilta-cel arm.
“The depth and durability of response observed with cilta-cel is something not observed with any other modality and is important for long-term outcomes such as progression-free survival and of course, overall survival,” said Dr Schecter.
"
The sense of the panel’s discussion here has been that there are issues upfront, but they are small, and perhaps balanced by the long-term benefits.
FDA Concerns
The FDA raised concerns over the lower overall survival (OS) in the first 10 months of treatment in the cilta-cel arm compared to the standard care arm. In the first 10 months of treatment, 14% of patients died in the cilta-cel arm, whereas 12% died in the standard care arm.
Additionally, 4.8% of patients in the cilta-cel arm died prior to receiving CAR-T therapy and 0.5% of patients in the standard care arm died before treatment.
“One might consider that since the subject did not receive cilta-cel, there is no treatment causality,” said Helkha Peredo-Pinto, MD, a clinical reviewer for the FDA, during the meeting. “However, it is [a] consequence of proceeding to receive treatment in the investigation arm. In this case, [the] CAR-T product, therefore, is relevant to the subject outcome.”
The FDA noted that it is the responsibility of Janssen Biotech, Inc. to demonstrate or prove that a more adequate bridging therapy regimen has the capacity to prevent death or early progression of disease. Additionally, the FDA stated that data are too immature to draw a conclusion about the OS benefit of cilta-cel.
“It represents a challenge for the agency to make a conclusive regulatory decision based solely on a speculative assessment of the benefit-risk profile rather than robust scientific evidence,” Dr Peredo-Pinto said.
Discussion
Based on the trial data, the FDA proposed 2 questions for the committee to discuss. These included:
- Whether the results of the CARTITUDE-4 trial are sufficient to support a positive risk-benefit assessment of cilta-cel for the proposed indication; and
- Whether the risk of early death associated with cilta-cel treatment is acceptable in the context of the PFS benefit.
Some committee members mentioned that the imbalance in early OS seemed to be a case of front-loaded risk, and that providers should be encouraged to inform patients of this before treatment.
“The curves really remind me of transplant related toxicities that are high early on,” said Mary Kwok, MD, clinical associate professor at the University of Washington School of Medicine.
Additionally, some members mentioned that cilta-cel is an important consideration for early treatment because it would allow patients periods of nontreatment and a higher quality of life.
“We can’t understate the ability of individuals to have this period of nontreatment that allows them higher quality of life — that the data did support — and moving into a disease-free state,” Susan Lattimore, RN, a nonvoting member of the committee and consumer representative, stated during the meeting.
“The sense of the panel’s discussion here has been that there are issues upfront, but they are small, and perhaps balanced by the long-term benefits,” said Ravi Madan, MD, chair of ODAC, during the meeting. Dr Madan also noted that bridging therapy and protecting patients against infection are areas for further research and development to optimize cilta-cel treatment.
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The American Society of Clinical Oncology (ASCO) has released guidelines for the use of cannabis and cannabinoids in adults with cancer. The guidelines were published in the Journal of Clinical Oncology, and a related Q&A article was published in JCO Oncology Practice.1,2
The guidelines note that cannabis and/or cannabinoids are increasingly being used by cancer patients, but data to support the efficacy and safety of these products remain limited.
The guidelines recommend that clinicians facilitate conversations with patients about their interest in or current use of cannabis and/or cannabinoids to prevent side effects or drug-drug interactions.
Cannabis and cannabinoids should not be used to augment or replace cancer treatment, but they may improve chemotherapy-induced nausea and vomiting when other guideline-recommended options have been exhausted.
Recommendations and Evidence
Health systems and clinicians should provide adult cancer patients with educational resources on cannabis and/or cannabinoids to enable communication and shared decision-making between patients and clinicians (good practice statement).1
Clinicians should routinely and without judgment ask adult cancer patients if they are interested in cannabis and/or cannabinoids, and, if so, provide guidance or resources (based on a good practice statement).1 This recommendation is based on data that suggest anywhere from 20% to more than 40% of adults with cancer may use cannabis products.2
If patients are using cannabis and/or cannabinoids outside of recommendations or evidence-based indications, clinicians should educate patients on recommended use and seek to minimize harm (good practice statement).1 Serious side effects of cannabis products include tachycardia, orthostatic hypotension, severe confusion, and paranoia, which may be more prominent in older adults or those naïve to cannabis and/or cannabinoids.2
Clinicians should advise patients against using cannabis and/or cannabinoids in place of cancer-directed treatment (a strong recommendation based on very low-quality evidence).1
Likewise, cannabis and/or cannabinoids should not be used to augment the effects of cancer therapies, unless being studied as part of a clinical trial (a weak recommendation based on very low quality evidence).1 This is based on a lack of data regarding potential drug-drug interactions in the cancer setting and the impact of these interactions on cancer treatment outcomes.2 In addition, studies have suggested that cannabis and/or cannabinoids may worsen immunotherapy outcomes, including progression-free survival and overall survival, although more data are needed.
If patients are receiving cancer treatments that are moderately or highly likely to cause nausea and vomiting and the patients experience symptoms that are refractory to standard antiemetic treatments, their antiemetic regimen can be augmented with dronabinol, nabilone, or a quality-controlled oral 1:1 THC:CBD extract (weak recommendations based on low- to moderate-quality evidence.1
Unless they are enrolled in a clinical trial, adults with cancer should not take 300 mg or more of oral CBD daily to manage symptom burden (a weak recommendation based on low-quality evidence). This is due to a lack of proven efficacy and the risk of reversible liver enzyme abnormalities, which were observed in a study of adults and children without cancer.
Oral cannabis products have a variable onset from 30 minutes to 2 hours, and effects may last from 5 to 8 hours, so dose stacking should be avoided to prevent side effects.
The guidelines also note that there is insufficient evidence to recommend for or against cannabis and/or cannabinoids in managing cancer treatment-related toxicities or symptoms, including pain, aside from the aforementioned clinical settings or in a clinical trial setting.1
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Instead of adding even more burdens to medical practices, artificial intelligence (AI) technology promises to become a tool for a host of clinical needs.
For example, a new report published in JAMA Network Open suggests that AI technology can significantly change medical practice. Physician investigators at Beth Israel Deaconess Medical Center in Boston, Massachusetts, compared a chatbot’s probabilistic reasoning to that of human clinicians. The findings suggest that AI could serve as a useful clinical decision support tool for physicians.
Lead author Adam Rodman, MD, an internist at Beth Israel, said clinicians struggle with probabilistic reasoning, the practice of making decisions based on calculating odds. He and his colleagues evaluated probabilistic reasoning in isolation. They used a previously published national survey of more than 550 practitioners performing probabilistic reasoning on 5 medical cases. Dr Rodman’s team fed the publicly available large language model (LLM) Chat GPT-4 the same series of cases and ran an identical prompt 100 times to generate a range of responses.
The chatbot was tasked with estimating the likelihood of a given diagnosis based on patients’ presentations. Then the chatbot program updated its estimates after given test results, such as chest radiography for pneumonia, mammography for breast cancer, stress test for coronary artery disease, and a urine culture for urinary tract infection.
When test results were positive, it was almost a draw. The chatbot was more accurate in making diagnoses than human clinicians in 2 cases, similarly accurate in 2 cases, and less accurate in 1 case. When tests came back negative, however, the chatbot demonstrated greater accuracy in making diagnoses than human clinicians in all 5 cases.
Probabilistic Reasoning
“I was surprised by these findings,” Dr Rodman said. “Humans do a very poor job at probabilistic reasoning. Whether it's playing poker, being more scared of flying on an airplane than driving on the highway, filling out an NCAA tournament bracket, or for my purposes predicting whether or not a patient has a pneumonia. We have known about innumeracy for a very long time.”
LLMs are effectively word or token prediction engines built off massive amounts of human text. But they also have emergent properties and may help with differential diagnoses. “In terms of routine use, I think physicians will first interact with LLMs in so-called ‘clerical’ tasks, serving as an AI scribe while in the clinic, assisting with discharge summaries, assisting with many of the other rote tasks that can take up so much time in the day,” Dr Rodman said.
Over the next several years, Dr Rodman said, he expects AI to start making a significant impact in clinical care in the form of clinical decision support. “I imagine LLMs that serve as a co-pilot, looking for early signs of medical errors, making suggestions on additional information to collect or additional diagnoses to consider or even taking the first pass at collecting a history,” he said.
During graduate school at Stanford University in Palo Alto, California, Sarah Hooper, PhD, developed ways to improve the automated processing of cardiac MRIs. Now, as a research scientist at the National Heart, Lung, and Blood Institute’s Imaging AI program, she is working to integrate machine learning across a variety of imaging platforms.
Dr Hooper said machine learning can be inserted into any point of the imaging pipeline to make things more efficient. One program might make it easier to automate parts of the analysis workflow so that a radiologist can spend 5 minutes looking at an image instead of 30. That all translates into patients getting results faster, according to Dr Hooper.
Predicting Cancer Outcomes
Researchers at UT Southwestern Medical Center in Dallas have developed an AI model that analyzes the spatial arrangement of cells in tissue samples. This approach, detailed in Nature Communications, accurately predicted outcomes for cancer patients, marking a significant advancement in using AI for cancer prognosis and personalized treatment strategies.
Tissue samples analyses by pathologists is time-consuming, and interpretations can vary among pathologists. In addition, the human brain can miss subtle features present in pathology images that might provide important clues to a patient’s condition. The new AI model mimics how pathologists read tissue slides, starting with detecting cells in images and their positions. From there, it identifies cell types as well as their morphology and spatial distribution, creating a map in which the arrangement, distribution, and interactions of cells can be analyzed.
The investigators successfully applied this tool to 3 clinical scenarios using pathology slides. They now hope to adopt this model to streamline targeted preventive measures for high-risk populations and optimize treatment selection for individual patients.
Investigators at Arizona State University School of Biological and Health Systems Engineering in Tempe are using AI to sort through decades of medical data to identify treatments for neurological disorders. They are also applying AI models to learn how cancer cells replicate and find solutions to keep older adults safe from life-threatening falls.
One of the investigators, associate professor Bradley Greger, PhD, said that for individual patient care, AI will be useful in digesting large amounts of data from multiple tests, physical exams, and imaging to aid clinical decisions. “Just like any technology, MRI, X-ray, ECG, blood tests, etc., AI can help to improve outcomes for patients through reducing morbidity and mortality,” Dr Greger said.
Dr Rodman agrees and said there are many examples where AI may help improve outcomes and possibly quality of life. “I can imagine a few ways language models can help with morbidity and mortality in the short-to-medium run. The first is in medical errors,” he said. “The second is in minimizing misdiagnosis and delayed diagnosis. We already have good experimental data that LLMs can make diagnoses better than humans and I'm running studies now showing how the use of LLMs actually changes human behavior,” said Dr. Rodman.
Patient Triage
Within the next several years, he envisions there will be human trials with AI providing a "second opinion." AI is perfectly suited for triaging patients and patient navigation. Health systems have a vested interest in both triaging patients to the right place for safety, and navigating them to the right place for efficiency. These systems currently rely on a considerable amount of manpower.
Triage decisions are high stakes, so there would need to be a high bar for evidence to show that LLMs can perform in this domain, Dr Rodman said. “But that’s what is exciting. Even if imperfect, their ease of use and ability to be integrated into clinical workflows could theoretically make humans make better decisions.”
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Stereotactic ablative body radiotherapy (SABR) is safe and effective treatment for older patients who have kidney cancer but are not suitable candidates for surgery, according to a recent study.
The new finding is from the phase 2 prospective, nonrandomized TransTasman Radiation Oncology Group (TROG) FASTRACK II trial (ClinicalTrials.gov ID: NCT02613819). Besides an exceptional cancer control rate for relatively large cancers (average 4.7 cm), there were no cancer-related deaths and only modest renal function decline after treatment, said lead investigator Shankar Siva, MBBS, PhD, a radiation oncologist who presented the findings at the American Society for Radiation Oncology (ASTRO) 2023 Annual Meeting. There is a significant unmet need for curing patients with tumors of these sizes, and these new findings point to the potential of radiation therapy to address that need, he said.
“Our trial benchmark for success was a control rate of greater than 80%, and we were pleasantly surprised that there was a 100% control rate, which is unprecedented in cancers of this size,” said Dr Siva, a professor in the Department of Radiation Oncology at the Peter MacCallum Cancer Centre in Melbourne, Australia. He noted that older patients with primary renal cell carcinoma (RCC) have unique challenges that make it difficult to treat them surgically.
“We are able to offer a new novel standard of care,” Dr Siva said. “This is the largest trial of a nonsurgical curative option in patients with primary RCC.”
The trial included 70 patients with a median age of 77 years. All had inoperable, high-risk kidney tumors or declined surgery. The median follow-up was 42 months. The majority of patients were male (70%) and the median body mass index was 32 kg/m2. The median Charlson comorbidity score was 7; the median RENAL complexity score was 8.
SABR was delivered in 1 or 3 sessions at 7 Australian centers and 1 in the Netherlands. Treated tumors on average were 4.7 centimeters. Of the 70 patients, 23 who had tumors smaller than 4 cm received a single fraction of radiation and 47 who had tumors larger than 4 cm received 3 fractions. No patient experienced local failure or died from their cancer. Dr Siva said. Freedom from distant failure was 99% at 1 and 3 years. Overall survival was 99% at 1 year after SABR and 82% at 3 years.
Adverse events (AEs) were relatively modest, with no grade 4 or 5 toxicities observed. However, 7 patients (10%) experienced grade 3 adverse events, most commonly transient abdominal pain (3 patients). In this study, 51 patients (73%) had a grade 1-2 treatment-related event and 11 patients (16%) experienced no AEs.
The average estimated glomerular filtration rate (eGFR) declined by 10.8 mL/min/1.73 m2 at 1 year and 14.6 mL/min/1.73 m2 at 2 years after treatment, indicating mild-to-moderate kidney stress. Only 1 patient required dialysis following treatment. Kidney function decreased modestly, leveling off after 2 years, Dr Siva said. “Most of these patients did not have a curative option,” Dr Siva said.
The findings justify designing a randomized phase 3 trial to compare SABR with surgery as the primary treatment modality for patients with operable kidney cancer, he said.
“The outcomes were excellent, with a very good toxicity profile, including transient grade 3 side effects and mild drop in renal function,” said Anand Mahdevan, MD, from the Department of Radiation Oncology at NYU Grossman School of Medicine in New York. “Future randomized trials for local therapy of kidney cancer should include SABR as a therapeutic option.”
“We now have the first international, multi-center prospective clinical trial in this space,” said Rohann Correa MD, PhD, of the London Health Sciences Centre in the Ontario, Canada. As far as Dr Correa is aware, there is not a comparable level of evidence for any other ablative modalities, particularly for tumors larger than 3 cm.
The trial provides sufficient evidence to influence clinical practice for patients who are unable or unwilling to undergo surgery, Dr Correa said.
Ellen Kim, MD, MPH, Director of Clinical Informatics in the Department of Radiation Oncology at Dana-Farber Cancer Institute in Boston, Massachusetts, noted the trial is relatively small, with only 70 patients. However, patients were recruited from 8 centers over nearly 4 years. “When available, SABR should certainly be considered for medically inoperable patients with this disease,” Dr Kim said. Future studies will be needed to confirm long-term safety, efficacy, and optimal SABR treatment techniques (such as dose/fractionation, immobilization, and expansion), she said.
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