Clinicians may soon have a tool that provides more accurate prognoses for individuals diagnosed with amyotrophic lateral sclerosis (ALS).
The prediction model incorporates eight factors significantly associated with a composite endpoint of noninvasive ventilation for more than 23 hours per day, tracheostomy, or death.
Improved timing of clinical interventions and stratifying of participants in future clinical trials are additional goals of the study, which included 11,475 patients with ALS across nine European countries.
The goal is for “medical doctors to provide predictions of survival for individual patients with ALS at the day of diagnosis. Before the development of our model, estimates of survival were mainly based on survival times in groups of patients,” study investigator Henk-Jan Westeneng, MD, from the Brain Centre Rudolf Magnus, University Medical Centre, Utrecht, the Netherlands, told Medscape Medical News.
“In these [previous] studies, the median survival time after onset of weakness was around 3 years. In our study…we showed that a reasonable proportion of patients substantially deviate from this median survival time,” he added.
The study was published online March 26 in Lancet Neurology.
Getting Personal
There is no cure for ALS. Survival rates can vary widely from several months to a decade or longer. Finding no sufficiently powered prediction tool based on individual risk, lead author Westeneng and colleagues identified 16 clinical, cognitive, and genetic prognostic factors from individual reports in the literature.
Data collection ran from 1992 to 2016 at 14 specialized ALS centers. Median follow-up was slightly longer than 8 years. The primary outcome was the time between ALS symptom onset and the composite endpoint.
Next, they performed backward elimination in the largest dataset with 1936 patients to select the most appropriate factors for the prediction model. They validated each selection through a series of bootstrap analyses.
Age at onset, diagnostic delay and the slope of revised ALS Functional Rating Scale scores (each validated in 100% of bootstraps), C9orf72 repeat expansion (87%), bulbar onset of ALS (81%), forced vital capacity (76%), definite ALS (71%), and presence of frontotemporal dementia (74%) were the eight factors included.
“Most of these predictors can be collected cheaply, simply, and non-invasively, rendering them useful for the assessment of individual prognosis in an outpatient clinic setting,” the authors write.
Sensitivity analyses demonstrated the accuracy of the prediction model when patient-level information about the presence of frontotemporal dementia or a C9orf72 repeat expansion was unavailable.
Investigators created five prognostic categories based on distinct median predicted survival times and observed times to the composite endpoint.
Table. Predicted vs Observed Composite Survival
| Survival | Predicted Outcome (mo) | Observed Outcome (mo) |
|---|---|---|
| Very short | 17.7 | 16.5 |
| Short | 25.3 | 25.2 |
| Intermediate | 32.2 | 32.8 |
| Long | 43.7 | 44.6 |
| Very long | 91.0 | 85.6 |
Implications for Care
“The patients with the shortest predicted survival, 20% of the studied population of 11,475 patients, have less than a 10% chance to survive more than 3 years after onset,” Westeneng said. “On the other hand, patients with the longest predicted survival, 20% of the studied population, have a greater than 90% change to survive more than 3 years.”
“Prediction models are important tools in the era of personalized medicine and can help medical doctors to tailor care to individual patients. Our model can, for example, be used to select care paths based on the predictions provided,” he added.
An internal-external cross-validation confirmed the generalizability of the model across different populations and settings. The authors also externally validated the findings in a second stage of the research using outcomes and other data from additional centers that treat patients with ALS.
With no guidance in the literature on the ethics of such tailored predictions for ALS survival, the authors looked to evidence regarding cancer prognoses.
“Early discussions about goals of care are associated with better quality of life, reduced use of non-beneficial medical care near death, enhanced goal-consistent care, positive family outcomes, and reduced costs,” the researchers note. They also acknowledge the distinction that many cancers have multiple treatments available, whereas ALS remains incurable.
To learn more about patient counseling preferences, the researchers surveyed Dutch patients with ALS. According to an online survey, 65% of 128 patients would like to know a reliable individual estimate of their survival, 20% would not, and 15% said they do not know.
When asked when they prefer to discuss their prognosis with their physicians: 29% would want to know at time of diagnosis/first consultation; 21%, at the second visit; and 35%, at another consultation; the remaining 15% had no preference.
“Our online model is ethically sensitive and demands thoughtful implementation,” the authors write. “It might support clinicians in helping patients to maintain a degree of autonomy and help them in planning their lives.”
Free Online Tool
The model will be free and available online but is intended only for physician use “to minimise the risk of potential harm to patients if the prediction they receive is shorter than expected.”
The findings also carry implications for future ALS research.
“The outcomes of this study have the potential to facilitate tailored care and trial design, which will hopefully lead to a more successful discovery of effective treatments for patients with this devastating disease,” the researchers note.
A potential limitation of the study is the researchers did not account for riluzole (Rilotek, Rhône Poulenc Rorer), an agent associated with improved ALS survival, as a predictor in the model.
“We will continue to advocate a patient-centered approach and to focus on our ultimate goal: curing ALS. Research in ALS is a fast-evolving field, but as long as people die because of this disease, more urgency for finding a cure is needed,” Westeneng said.
“We will therefore study how our model can improve clinical trial design. This will hopefully increase the power of new clinical trials and thereby the chance to find new treatments for ALS. Furthermore, several other follow-up studies will be conducted.”
Kudos, Caveats
In an accompanying editorial, Hiroshi Mitsumoto, MD, from The Eleanor and Lou Gehrig ALS Research Center at Columbia University Medical Center in New York City, notes that “kudos should be given to the European ALS research community for gathering the large amount of information on patients that made the study possible. However, the ability of the model to prognosticate is not as precise as one would hope, because it provides a fairly wide range of survival times.”
“This report raises new questions about how diagnoses and prognoses should be conveyed to patients,” he writes. “I have seen many patients with this disease over the years, but discussing the diagnosis and prognosis has never become routine. This discussion, in my experience, is difficult and stressful because the utmost sensitivity is required for the delivery.”
“One of the unique contributions of this study is that the model is accessible online. The investigators thoroughly discussed the ethical sensitivity required to protect patients who might become distressed upon learning their prognosis,” Mitsumoto continues. “Therefore, the model is only currently available to physicians; yet, we know well that nothing can be hidden if a system becomes available online.”
“In the end, the ALS community absolutely welcomes this scientific achievement,” he says. “However, doctors who use this model must always keep patients in mind and use this information with great care and sensitivity.”
The Netherlands ALS Foundation funded the study. Dr Westeneng has disclosed no relevant financial relationships. Dr Mitsumoto disclosed he receives grants from the National Institutes of Health, Muscular Dystrophy Association, Spastic Paraplegia Foundation, and Centers for Disease Control and Prevention. He also receives grants and personal fees from Cytokinetics; personal fees and other funding from Mitsubishi-Tanabe; and personal fees from Denali and Biohaven.
Lancet Neurol. Published online March 26, 2018. Abstract, Editorial
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