By Deborah Borfitz 

September 3, 2024 | A first-ever nationwide clinical trial examining the health-related quality of life (QoL) trajectory of young Hodgkin lymphoma patients undergoing treatment is “on the cusp of a new wave of measurement that is far more accessible and interpretable” for cancer patients and their physicians than clinical measures like number of relapses and overall survival, according to Susan Parsons, M.D., MRP, director of The Center for Health Solutions at the Institute for Clinical Research and Health Policy Studies and medical director of the Reid R. Sacco Adolescent and Young Adult Cancer Program at Tufts Medical Center.  

Not only did the addition of an immuno-oncologic agent to a multidrug chemotherapy backbone prove to be clinically superior to standard chemotherapy (New England Journal of Medicine, DOI: 10.1056/NEJMoa220666); it was also found to have fewer negative effects on patients’ QoL than standard treatment (Journal of Clinical Oncology, DOI: 10.1200/JCO.24.00038). Hodgkin lymphoma has for decades had “outstanding survival outcomes for the majority of patients... [but] the treatment tradeoffs are very dramatic” in terms of toxicities experienced many years later from front-line therapy, says Parsons. “Providers are constantly searching for ways to preserve survival but also to reduce the risk of late effects so that people don’t have to suffer in their survivorship.”  

For the latest study, patients were randomly assigned to the standard multidrug chemotherapy regimen with or without the addition of an anti CD30 antibody-drug conjugate (brentuximab vedotin), which had been shown in previous trials to be associated with an increased risk of peripheral neuropathy. Two brief, targeted, and paper-based QoL questionnaires—one addressing the impact of neuropathy and the second on overall quality of life—had “extraordinarily high participation at almost all time points,” notes study lead AnnaLynn Williams, Ph.D., assistant professor of surgery at the University of Rochester Medical Center and a member of the cancer prevention and control research program of its Wilmot Cancer Institute (Journal of Patient-Reported Outcomes, DOI: 10.1186/s41687-023-00653-0). 

This was a clear demonstration of the possibility and importance of assessing QoL and other patient-reported outcomes in nationwide clinical trials, adds Parsons, and will enable the development of many similar studies in Hodgkin lymphoma and several other diseases. The research team is now collaborating with several other groups in discussions with the National Cancer Institute (NCI) and the U.S. Food and Drug Administration about how to incorporate the patient experience into the drug approval process across the entire age continuum. “It’s complicated, but I think it’s the future,” she says.    

Williams agrees, citing increased interest in QoL measures coupled with new technologies making it easier to collect the data. “We now have the luxury to care about [quality of life] for certain types of cancers that have very high survival rates,” she says. 

Job one was to keep patients alive, says Parsons, reciting the words once uttered by one of her clinical teachers. “Now, the conversation has shifted... [to] the secondary question... ‘At what cost?’  and ‘How can we do better?’” 

Historically, the prevailing view was that collecting QoL metrics in either clinical trials or clinical care was incredibly burdensome, Parsons says. The current reality is that new measurement systems, developed through initiatives of the National Institutes of Health and available free of charge, allow QoL to be efficiently and precisely assessed. “There’s no excuse not to access them and incorporate them thoughtfully into trials or practice.” 

Patient-defined Metrics

Williams herself is a cancer survivor and underwent intensive therapy for acute myeloid leukemia as a young adult in 2008. The treatment came with a lot of toxic side effects that made it challenging to tolerate, she recalls. At the time, patients’ experience with treatment in clinical trials and medical practice wasn’t often captured by any means to reveal what they endured to survive.  

Parsons, who has been interested in this area of research for about 35 years now, says she has seen perceptions about QoL measurement change over time. “My initial interest was in caring for children going through allogeneic stem cell transplant through really demanding treatment and... the experience that they went through in surviving that transplant really wasn’t captured by any of our clinical metrics.” 

Treatment for Hodgkin lymphoma, in contrast to something as arduous as an allogeneic stem cell transplant, is “quite short,” she notes, typically between six and nine months if patients respond to front-line therapy. “Although disease outcomes are very favorable, the initial diagnosis and presentation can be quite dramatic.” 

Many patients present with acute respiratory embarrassment—whereby the respiratory system is unable to properly transfer oxygen from the atmosphere to the blood or remove carbon dioxide from the blood—have compression of their airways, and experience symptoms such as weight loss, night sweats, and persistent fevers, she explains. It “definitely impairs people’s quality of life.” 

For this reason, the latest study deliberately included a global measure of quality of life as opposed to more granular aspects of it like physical, social, or emotional functioning, says Parsons. “That reflected the era in which we planned the study, which was more than 10 years ago when there wasn’t the same degree of fluency or comfort with these measures... we didn’t want to overwhelm [clinicians] with the details provided by individual domain scores.” More refined QoL measures capturing the daily life experiences of patients are now being used in ongoing intervention trials.   

One of the goals here is to “provide clinicians with a broader appreciation of what patients are willing to go through and do go through as a result of these treatments,” Parsons says. The other objective is to “provide more anticipatory guidance to patients to say we know these next few weeks or next couple of months are going to be really difficult, but patients like you tell us that things get better towards the middle treatment or at the end of treatment, or whatever the results might be.” 

In addition to giving physicians a way to frame the information so that patients better know what to expect, she continues, the inclusion of QoL metric in clinical trials enables a comparison of the various treatment options based on patient-defined metrics. Ultimately, that translates into greater choice for individual patients and the clinicians with whom they are having these discussions. 

Contextualizing Clinical Measures

The pursuit of novel therapies and a reduction in radiation exposure are important, but in terms of quality of life and the patient's experience during treatment almost all the research to date has been limited to adults with Hodgkin lymphoma, says Williams. Pediatric and adolescent patients have been under-characterized, “despite having data from very long-term survivors... that suggested in the long-term setting they were experiencing deficits in their quality of life.” 

That Hodgkin lymphoma has such high survival rates, often over the long term, makes QoL assessments even more important, she adds. “If we’re showing marginal gains in survival between an experimental arm and a standard arm, how do you advise patients on which [treatment] they should be taking? Things like quality of life and their toxicity profile help us to do that.” 

Except for a couple of large survivor studies, most studies that have looked at long-term survivors of Hodgkin Lymphoma have included quite small samples, notes Parsons. Cross-sectional studies, which provide “more of a snapshot of how people are doing,” reveal a recurring theme of persistent fatigue and diminished quality of life but “do not provide any information about the experience of life at the time of initial diagnosis or through front-line therapy, so we didn’t know if this was a survivor problem or a problem that was evident all the way through diagnosis, initial treatment, and then transition into survivorship.” 

The latest study provides “a movie about what it was like from the beginning,” rather than individual photos of the patient's experience at a particular time point, Parsons says. As it turns out, “quality of life is impaired in the beginning for a subset of patients, and it gets better for the majority... of those patients and helps us put some context around that.” 

Measures and Means

On both the pediatric and adult side, many differences have historically existed in the way quality of life gets measured and incorporated family caregivers in the perceptions of patient’s well-being, says Parsons. One of the significant happenings nationally over the past two decades is the number of initiatives led by the National Institutes of Health (NIH) to “really up our game” in terms of standardizing QoL measurement tools. 

Perhaps the best known among these is the Patient-Reported Outcomes Measurement Information System (PROMIS), an initiative that began in 2004 across all NIH institutes and disease areas, she says. PROMIS gathered investigators who wanted to improve measurement and the ability to incorporate these tools in clinical research and at the point of care to inform clinical practice. “The tools are wonderful because they’re brief, some having as few as four questions or as many as eight to 10 questions but take a typical patient one to two minutes to complete.” 

When one of these PROMIS tools was first introduced in her clinic a decade ago among adolescents and young adults with cancer, the big fear was that the questionnaires were going to slow down clinic flow and patients and caregivers would be upset. “The reality was nobody was upset... we scored the measure immediately and used [it] in our clinic to inform the care,” Parsons says. 

Recently, as part of the NCI’s Clinical Trials Network, Parsons and her colleagues put forth a consensus-based measurement approach to QoL assessment for clinical trials that involve adolescents and adults, advocating for inclusion of different PROMIS short forms as well as symptom assessments using other comparably validated measures, she continues. The proposed platform had “tremendous buy-in nationally,” suggesting QoL measures will more often be successfully included in clinical studies moving forward. 

“We have our work cut out for us, because the data are only as good as the ways we collect it,” says Parsons, adding that her group has been exploring ways to “streamline data collection so we don’t have missing data, which is a statistical nightmare due to the bias they introduce.” Electronic data capture and multimodal data collection systems are being explored. “We’ve been encouraging researchers to be really thoughtful about what the actual study question is related to patient-reported outcomes, so they are not doing a massive descriptive study within the context of a clinical trial but... [rather addressing] what is it about this trial and these drugs that need a quality-of-life question added.” 

The latest study aids in these efforts by “setting a precedent for our ability to include [QoL] measurement like this,” says Williams. The “amazing part” was that response rates were above 90% for the first three time points—before treatment and at treatment cycles 2 and 5—before tapering off a bit (to 77%) at the fourth time point at the end of therapy. What the researchers learned in executing the study is that “we need to be thoughtful about the time points for collection of these patient-reported outcomes so that it is... easier for people to complete them,” for example by timing them with a clinic visit or a normal point of contact during the study. 

Overall, the study had “low missingness for the majority of timepoints,” even though it was done with paper and pencil, Williams says. Participation rates could well be higher in trials using electronic versions of the questionnaires and giving participants options regarding how they complete the surveys.   

Progress made in advancing the idea of embedding QoL measurements directly into drug trials was made possible by continued support from the Leukemia & Lymphoma Society, a key sponsor of the latest study, notes Parsons. Financial support also came from the NCI and the Seagen Corporation, which helped facilitate data collection and provided the study drug.