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Why Paint from a Limited Palette in Cancer Clinical Trials?

Summary in Thirty Seconds

  • Cancer clinical trials often focus on a limited number of outcomes, missing the full impact of a new compound on a person's life and perspective.

  • Health-related quality of life (QoL) measures can be used to assess this perspective, and ASCO and ESMO recommend incorporating QoL measurements as part of the endpoints of clinical trials. Including QoL as an outcome may help paint a more complete picture of the impact of a new cancer compound tested in a CCT.

  • QoL measures reflect patient satisfaction and the perceived benefits of an experimental compound, which are not necessarily captured by more commonly used CCT endpoints such as Overall Response or Progression-Free Survival.

  • QoL measures include patient perspectives such as functional health, well-being, and psychological issues. Composite measures have been developed to assess the impact of QoL on the outcome of different therapies.

  • Future research and policy recommendations should consider not just short-term QoL outcomes but QoL outcomes throughout the patient's cancer.

Monochrome versus Polychrome

Painting a picture with one or two colors might be considered quite daring and artistic and may have a specific purpose, but doing so rarely captures the complete essence of the scene. Using a broader color palette is key to fully portraying the complexity of the picture. Similarly, cancer clinical trials can get stuck in selecting from a limited number of outcomes, thus missing large aspects—and some nuances—that a new compound has on the life and perspective of a person with cancer.

Quality of Life (QoL) as an Outcome in Cancer Clinical Trials

People with cancer have varied perspectives on the importance of quality versus quantity in the treatment and course of their illness. Health-related quality of life (QoL) measures can both qualitatively and quantitatively assess such a perspective. As the focus of Cancer Clinical Trials (CCTs) has shifted to more patient-centric care, interest in QoL measures has gained traction. In recent years, ASCO and ESMO have recommended the incorporation of QoL measurements as part of the endpoints of CCTs.[1],[2] QoL measures reflect both patient satisfaction and the perceived benefits of an experimental compound, which are not necessarily captured by more typically used CCT endpoints (e.g., Complete Response, Overall Survival, Progression-Free Survival, etc.). Thus, QoL measures may otherwise demonstrate the efficacy of a new compound tested in a CCT; ASCO guidelines assert that QoL should be one of the multiple outcomes considered in a CCT because no single measure adequately or fully describes the outcome of cancer treatment.[3]

While QoL is measured in many types of clinical trials, such outcomes may be particularly important in CCTs, where the intervention may not be designed to cure the disease while only modestly prolonging life.[4] For example, the average increase in the overall survival of the new cancer drugs approved by the FDA and European Medicine Agency between 2003 and 2013 was 3.4 months.[5] Feld states, “Quality-of-life assessments might best be utilized in trials in which survival differences between treatments are expected to be small, which is frequently the case.”[6]

It has also been argued that a single cancer treatment metric like Overall Survival tells an incomplete story because it doesn’t capture the value given to all the participants in a clinical trial.[7] In such cases, improvement in QoL is an important consideration and may help paint a more complete picture of the impact of a new cancer compound tested in a CCT.

What Is QoL?

The WHO describes health-related QoL as “an individual’s or group’s perceived physical and mental health over time.”[8] QoL measures are part of Patient Reported Outcomes (PROs) that include a range of symptoms, such as functional health, well-being, and psychological issues from the patients’ perspective, without interpretation by a clinician.[9],[10] Notably, many of these symptoms and functions are not readily measurable (or feasible) with laboratory tests or imaging procedures; rather, they fall in the category of patient-reported outcomes (PROs). Some examples are role functioning, social functioning, sexual functioning, appetite, difficulty concentrating/focusing, sense of well-being, pain, and fatigue.[11] ASCO guidelines state, “Quality of life includes global quality of life, as well as its physical, psychologic, and social dimensions.”[12]

Rather than assess QoL as a stand-alone measure, composite measures have been developed to assess the impact of QoL on the outcome of different therapies.[13] Such measures have been increasingly used in cost-utility analyses of pharmaceuticals and various healthcare interventions; however, scenarios are often more complex, with disease and treatment effects impacting QoL variably over the progression and remission of cancer. While tumor-specific therapy can potentially prolong life, it may also reduce QoL significantly. Some patients are willing to endure treatment-associated toxicities to increase their length of life, while others value QoL more and emphasize quality over quantity.[14]

What Influences QoL?

A study of QoL in almost 200 people with cancer who were undergoing a variety of cancer treatments looked at what factors influenced QoL outcomes. Higher tumor stage, poorer everyday functional status (as measured by ECOG), higher rates of adverse effects, and female sex were associated with poorer QoL. Overall, people in the study had poorer QoL scores in functional well-being areas and higher QoL scores in social/family well-being.[15] Another study of 200 people with cancer found a significant difference in the QoL of patients with less than 2 chemotherapy cycles compared to those who underwent 3 or more cycles.[16]

A retrospective review of 45 phase 3 CCTs involving almost 25,000 subjects found improvement in global QoL for participants taking the experimental agent in 24% of trials. Those CCTs with improved QoL were more likely to also show improved Overall Survival compared to trials with unimproved QoL.[17] A review of 39 CCTs found that in 36 of 39 trials, at least one PRO (QoL was the most common PRO) was significantly associated with survival, and in some cases, treatment response.[18]

Concern has been raised about the way in which QoL is assessed, such as that open-label studies will lead to bias in PROs including QoL; however, research has allayed this concern. One study evaluated the results of two CCTs assessing QoL and found no clear difference between open-label and blinded groups in terms of QoL self-reports. The authors concluded, “This study adds to the growing evidence demonstrating that concerns regarding open-label bias should not prohibit the interpretation of large and meaningful treatment effects on PROs.”[19]

QoL Evaluation over Time

QoL may not only be measured during or at the completion of a CCT or therapy, but it may also extend beyond intervention. A 2020 JAMA study evaluated the extent to which QoL is assessed in CCTs. The research analyzed 149 CCT studies that reported on QoL and found that 70% measured QoL during intervention, 46% reported QoL during follow-up, but only 3.4% did so until the time of death. Studies that reported a positive QoL outcome (i.e., more favorable QoL in the intervention group than in the control group) ranged from 52 to 57% of studies. However, of the studies reporting QoL until the end of life, most reported worse QoL outcomes for the intervention group than the control group. The authors concluded that “Future research and policy recommendations should consider not just short-term QoL outcomes but QoL outcomes throughout the patient’s cancer.”[20]

This conclusion is supported by Shrestha et al., who point out that while QoL may drop shortly after an intervention, as the effect of a treatment has its full impact, overall better long-term QoL may be seen as well as increased life expectancy. Therefore, they argue that QoL measurement should be measured over time rather than focused on a single time point when assessing an intervention.[21]

QoL and Immunotherapy CCTs

A review of longitudinal QoL outcomes in 26 studies of people with cancer taking immune checkpoint inhibitors (ICIs) found that QOL did not change over time in patients treated with ICIs, and higher QOL was seen in patients treated with ICIs versus non-ICI regimens. The only specific domain where people on ICI treatment fared worse than those on non-ICI regimens was in terms of insomnia severity.[22]

Another study specifically looked at programmed death receptor‐1/programmed death‐ligand 1 (PD‐1/PD‐L1) inhibitors (nivolumab, pembrolizumab, or atezolizumab) versus standard‐of‐care therapy in patients with advanced cancer. Of the over 6,000 patients from 13 CCTs included in this meta-analysis, people taking PD1/PD‐L1 inhibitors maintained better health‐related quality of life and had less worsening in symptoms than standard‐of‐care therapy even though patients on immune modulators were on treatment longer. The authors concluded that the better QoL profile—assessed through PROs—supports the clinical benefit of ICIs for advanced cancer.[23]

QoL Assessed in CCTs

A qualitative study of 40 women with recurrent ovarian cancer (42.5% of whom had prior enrollment in a CCT) found hope for clinical benefit and a desire to help others as the most common reasons for trial participation. QoL was also a key factor. While many participants expressed a willingness to sacrifice QoL for clinical benefit, others did not. The authors concluded that QoL information is highly desired before enrolling in a CCT and may potentially help increase CCT enrollment. The inclusion of PROs in developmental therapeutic trials may inform QoL for future patients and help diversify and improve representation in trial accrual.[24]

In a small study of QoL for people with stage III or IV lung cancer, three main domains of QoL were identified. The first domain was physical aspects/functioning (e.g., symptoms and side-effects including skin conditions, nausea, fatigue, risk of infections, sensory abnormalities, pain, and changes in physical appearance). Second, participants identified psychological aspects including uncertainties regarding their future health state and lowered autonomy and independence. Third, participants highlighted changes in social functioning (e.g., communication with healthcare providers, and social interaction with friends, family, and peers).[25] In a study of targeted therapy on over 700 people with non-small-cell lung cancer, those taking the therapy had improvement in three QoL domains (global QoL, role functioning, and physical functioning), and, unsurprisingly, those with a complete or partial response were more likely to show improved QoL.[26]

The Bottom Line

The outcomes of CCTs can be assessed in many ways. Often, these measures are quantitative and definitive, such as Overall Survival; however, such a measure may miss the important qualitative, functional features of a new compound’s effect on a person with cancer’s life. Quality of Life measures (QoL) provide such information and can help investigators better understand the patient’s perspective. QoL as a different outcome can be particularly important where the intervention may not be designed to cure the disease while only modestly prolonging life. Additionally, QoL may be measured longitudinally, where an intervention may initially produce a drop in QoL, but as the effect of a treatment has its full impact, overall better long-term QoL may be seen. Thus, QoL is an important facet to measure in CCTs as it helps paint a more complete and nuanced picture of the impact of an intervention on a person with cancer, both during and after the CCT.

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