Patient preferences in the treatment of stage III/IV classic Hodgkin lymphoma: Results from the CONNECT cross‐sectional survey

We explored patient front‐line treatment preferences in newly diagnosed stage III/IV classic Hodgkin lymphoma (cHL). The CONNECT patient survey, administered online from 30 December 2020 to 1 March 2021, examined preferences overall and by age at diagnosis in 182 adult patients diagnosed with stage III/IV cHL within the past 10 years in the United States. At diagnosis, patients' median age was 36 years; 66% of patients were younger (aged 16–41 years) and 34% older (aged 42–85 years). When asked about initial treatment goals, 74% of patients ranked cure as their first or second goal (86% younger vs. 52% older patients; p < 0.001). At diagnosis, 72% of patients preferred aggressive treatment, and 85% were willing to accept more short‐term risks in exchange for a better‐working therapy long term. For long‐term risks, younger versus older patients were significantly more concerned about second cancers (p < 0.001) and fertility issues (p = 0.007), whereas older patients were more concerned about lung damage (p = 0.028) and infections (p < 0.001). Most patients (94%) reported having a caregiver at some point, but 99% of these patients retained some control of treatment decisions. Collectively, these survey results highlight patient treatment preferences and differences in treatment goals and long‐term side effect concerns based on patient age.

Despite excellent survival, little is known about the patient journey following a stage III/IV cHL diagnosis in the modern era.Two patient preference studies were identified that assessed trade-offs for patients with cHL. 15,16A 2020 US-based, cross-sectional online survey found that patients rated survival attributes as more important than drugrelated toxicity when considering first-line treatments. 16imilarly, a 2019 survey carried out in Europe reported that 5-year survival attributes were more important to patients than short-term adverse effects. 15Moreover, the overall patient journey for those diagnosed with cHL, including their relationship with caregivers and physicians, has yet to be fully described in the literature.
Here, we present findings from a patient survey included as part of the CONNECT (Classical Hodgkin Lymphoma: Real-World Observations from Physicians, Patients, and Caregivers on the Disease and Its Treatment) study, the first real-world survey in cHL to include patients, physicians and caregivers.The objective of the patient survey was to understand the patient journey for those diagnosed with cHL, including cHL symptoms, diagnosis, treatment goals, concerns, decision-making and relationships with caregivers and physicians.Differences in treatment preferences by age were also explored.

Study design
The CONNECT study consisted of three distinct surveys, one each for patients, physicians and caregivers.The focus of this manuscript is the CONNECT patient survey.Results from the CONNECT physician 17,18 and caregiver 19 surveys have been published.The CONNECT patient survey was administered online from 30 December 2020 to 1 March 2021.The survey was developed based on constructs identified from the literature, with input from clinicians and patient experience research experts from Gryt Health.The CONNECT patient survey was developed for this study only and was not intended for future use as a validated instrument.
Patients were aged ≥18 years at the time of survey participation; aged ≥12 years at cHL diagnosis; diagnosed with cHL within the past 10 years; treated previously or currently for cHL in the United States; able to speak, read and write in English; and willing and able to participate in the survey.Here, we present data for those patients who self-reported being diagnosed with stage III/IV cHL at the time of initial diagnosis.Survey questions were asked regardless of the therapies the patient received or was receiving.
Patients were recruited via email invitations through an online panel (sourced through social networks, such as support groups, referrals and social media as well as the Gryt Health Cancer Community).Data were collected anonymously via a secure online data collection platform; the survey took approximately 25 min to complete.Respondents received a $50 electronic gift card for completing the survey.The CONNECT survey was reviewed by the New England Institutional Review Board and granted exemption status.
The CONNECT caregiver survey asked caregivers about their role in treatment decisions.Where possible, data from paired patients and caregivers were evaluated and are presented in this manuscript.Pairs were recruited from the Gryt Health Cancer Community.After a patient or caregiver completed the survey, they were provided an opportunity to nominate their caregiver (if patient) or patient (if caregiver) to take the survey.

Statistical analysis
Age at diagnosis was assessed by tertiles and subsequently analysed by younger versus older patient subgroups (younger patients: aged <42 years; older patients: aged ≥42 years); these subgroups correspond closely with the National Cancer Institute's adolescent and young adult definition cut-off of 40 years. 20Quantitative variables were summarised using mean and standard deviation and median and interquartile range.Categorical variables were summarised as individual totals and proportions.Non-mutually exclusive categorical variables were summarised as individual totals and a respective proportion out of the total sample size.Responses by age at cHL diagnosis (younger vs. older patients) were analysed and compared statistically at the 95% confidence level.

Patient characteristics
The survey was completed by 182 patients with stage III/IV cHL.The median age was 36 years, with approximately onethird of patients falling into each of these age groups at diagnosis: 16-27 years, 28-41 years, and 42-85 years (Table 1).A total of five patients participating in CONNECT were aged less than 18 years at diagnosis of stage III/IV cHL (16 years, n = 1; 17 years, n = 4).Sixty-four percent of patients were female, and 27% of patients were receiving treatment at the time of survey participation.

Symptoms and diagnosis
Overall, 70% of patients reported experiencing swollen lymph nodes, and 66% of patients reported fatigue prior to diagnosis (Figure 1).Symptoms experienced before diagnosis differed with age, with significantly more younger versus older patients reporting swollen lymph nodes (78% vs. 53%) and itchy skin (56% vs. 31%).When patients were asked about the symptoms experienced that led them to seek medical attention or treatment, swollen lymph nodes (53%) were most frequently selected (Figure 1).Presenting symptoms were found to vary by age, with a significantly higher percentage of younger than older patients seeking medical attention for swollen lymph nodes (64% vs. 31%), whereas a significantly higher percentage of older than younger patients sought medical attention for high fever (27% vs. 13%) and fatigue (34% vs. 18%).Approximately one-fourth of patients in both age groups reported drenching night sweats.
Of the 41 patients who reported night sweats, only 4 reported no other symptoms.Sixty per cent of patients initially visited their primary care physician to seek medical help for their symptoms.The median time from the first onset of symptoms to seeking medical attention was 1 month, and the time between the first onset of symptoms to receiving a cHL diagnosis was 3 months, with 92% of patients beginning treatment within 1 month of diagnosis (Figure S1).The median time to diagnosis from the first onset of symptoms was longer for younger than older patients (5 vs. 1 month; p = 0.001).COVID-19 impacts on delaying a cHL diagnosis were reported by 18% of patients (Figure S1).Concerns reported by 70% or more patients at diagnosis included treatment side effects (83%), disruption of life goals and plans (81%), treatment not working and/or cancer getting worse (75%), ability to feel 'normal' again (73%) and death (70%) (Figure S2).Concerns among younger and older patients differed, with younger patients being significantly more concerned about disruptions of life goals and plans (84% vs. 74%), treatment not working and/or cancer getting worse (77% vs. 71%), impacts on school or work (73% vs. 32%), informing their employer/school about their diagnosis (43% vs. 32%) and fertility (34% vs. 7%).Compared with younger patients, older patients were significantly more concerned about death (79% vs. 66%).

Treatment goals and preferences
When asked about top initial treatment goals, 74% of patients ranked cure as their first or second goal for initial treatment (Figure 2).When results were examined by age, younger patients were significantly more likely to rank cure as their first or second initial cHL treatment goal (86% vs. 52%; p < 0.001) than older patients.Compared with younger patients, older patients were significantly more likely to rank living longer (45% vs. 28%; p = 0.023) and having a better quality of life (27% vs. 8%; p = 0.001) as their first or second initial cHL treatment goal.When participants in remission (n = 116) were asked what was currently most important to them, staying in remission was ranked first or second by 85% of younger patients (90/105) and 100% of older patients (11/11).

Treatment aggressiveness
Overall, 72% of patients preferred to receive aggressive treatment at diagnosis, with 77% of younger and 63% of older patients reporting this preference (p = 0.3; Figure 3).While most patients (85%) were also willing to trade off greater short-term risks for a therapy that worked better over the long term, a significantly higher percentage of younger compared with older patients were willing to make this trade-off (93% vs. 71%; p < 0.001).Only 44% of patients in both age groups were willing to accept more long-term risks in exchange for a therapy that worked better over the long term.

Adverse effects
Most younger and older patients reported being informed about short-term (84% and 73%) and long-term (75% and 61%) side effects of treatment during discussions about cHL treatment options with their physician.More patients reported being informed about the short-term (80%) than long-term (70%) risks of cHL treatment.Significantly more younger than older patients reported that their physician mentioned the following short-term side effects: nausea/ vomiting (p = 0.017), hair loss (p < 0.001), fatigue (p < 0.001), risk of infection (p < 0.001), low blood count (p < 0.001), numbness and tingling (p < 0.001) and muscle weakness (p = 0.035; Figure 4A).For long-term effects, significantly more younger than older patients reported that their physician mentioned the risk of developing other cancers (p = 0.018) and infertility (p < 0.001), while significantly more older than younger patients reported that their physician mentioned stroke (p < 0.001; Figure 4B).

F I G U R E 3
Patient preference for treatment aggressiveness overall and by age.a Percentage of patients who selected 0-33 on a sliding scale that ranged from 0 to 100, with 0 meaning treating aggressively, with less concern for the management of short-term tolerability and side effects of treatment, and 100 meaning treating less aggressively, in favour of better management of side effects and greater tolerability to the treatment.b Percentage of patients who selected 'agree' for question shown.
When patients were asked about the long-term treatment effects of most concern (ranked 1 or 2), significantly more younger than older patients were concerned about the longterm risks of developing second cancers (p < 0.001) and fertility issues (p < 0.001), while significantly more older than younger patients were concerned about the long-term risks of lung damage (p = 0.028) and infections (p < 0.001; Figure 4C).

Relationship with caregiver and physician
Almost all patients (94%) had or previously had a caregiver to help them manage their cHL.Ninety-nine per cent of these patients retained at least some level of control in making their treatment decisions, including making their own decisions, making their own decisions after considering their caregiver's opinion, making decisions together with their caregiver or having the caregiver make the final decision, after hearing the patient's opinion.Most patients reported that they are the primary person to discuss treatment options with their physician (70%); 26% reported their caregiver is also involved (Figure S3).Among patients with a caregiver, a higher proportion of older than younger patients reported that their caregivers were involved in discussions with physicians on treatment options.
When patients were asked about the roles that they, their physician and their caregiver played in treatment decisionmaking, patients without a caregiver reported that they played a mean of 29% and their physician played a mean of 71% of the role in treatment decision-making.Patients with a caregiver reported that they played a mean of 37%, their physician played a mean of 45% and their caregiver played a mean of 18% of the role in treatment decision-making.Most patients (73%) discussed treatment options with their physician within a week of their diagnosis, and most patients (58%) were likely to rely on their physician to explain their treatment options before researching those options themselves.A majority of patients trusted their physician's treatment recommendations completely (79%) and felt comfortable voicing opinions about treatment to their physician (78%).Most patients also agreed with their physician about how aggressively to treat their cancer (81%).Patients reported that explanations about their treatment options from their physician were important, particularly regarding how medication side effects might affect them (90%), how potential side effects would be managed (89%) and how medications work (87%); these aspects were important to a greater extent for younger than older patients.

Caregiver and patient pairs
Fifty-three patient and caregiver pairs were surveyed as part of the CONNECT study; the caregiver for 49% of these pairs was a spouse or partner.Among the paired responses, the patients' median age was 29 years and the F I G U R E 4 Short-and long-term side effects discussed by physicians and long-term effects of concern to patients.(A, B) Patients were asked the following question: Did your healthcare provider tell you [insert short-term/long-term effect] side effect may be a risk of cHL treatment?(C) Patients were asked the following question: Which of the following long-term side effects are of greatest concern to you? Please rank the top 3. Responses shown reflect the percentage of patients who assigned a rank of 1 or 2 to the long-term effect.a Denotes significant differences between those aged <42 years and those aged ≥42 years.caregivers' median age was 40 years.The demographics and characteristics of paired and non-paired participants differed slightly, with both paired patients and caregivers being younger than those patients (age at survey: 29 vs. 56 years) and caregivers (40 vs. 49 years) who were not paired.Additionally, among caregiver-patient pairs, 94% of patients were in remission at the time of the survey, compared with 6.4% of patients for non-paired caregivers.At the time of initial diagnosis, among caregiver-patient pairs, approximately 49% of patients had stage III/IV disease; among non-paired caregivers, approximately 33% of patients had stage III/IV disease.
Among the matched caregiver-patient pairs, 66% of pairs agreed on their top treatment goal, with 94% of these pairs identifying it as cure.Overall, 13% of pairs agreed on all three of their top goals, 49% agreed on two of their top three goals and 38% agreed on one of their top three goals.

DISCUS SION
Results from the CONNECT survey, the largest known survey of patients, physicians and caregivers on cHL, provide insights on the patient journey, including factors and preferences surrounding diagnosis and treatment, as well as the importance of patients' relationships with their physicians and caregivers.The median time from the first cHL symptoms to seeking medical attention was 1 month.Symptoms that were most often experienced and led to seeking medical attention were swollen lymph nodes and fatigue; the prevalence of fatigue in this survey (66%) was notably higher than that reported for adults globally (approximately 20%). 21verall, among patients with stage III/IV cHL participating in this survey, 91% of younger and 94% of older patients began treatment within 1 month of diagnosis.
Patients were most concerned at diagnosis about treatment side effects, disruption of life goals and plans, treatment not working and/or cancer becoming worse, the ability to feel 'normal' again and death.These concerns highlight the importance of choosing a therapy with the greatest chance of achieving a cure in the front-line setting while minimising adverse effects.Differences in treatment goals were found between patients diagnosed with stage III/IV cHL based on age.While 74% of patients overall ranked cure as their first or second treatment goal, a significantly higher percentage of younger than older patients did so.Conversely, a significantly higher proportion of older than younger patients ranked living longer and having a better quality of life as their first or second treatment goal.
Although most patients, regardless of age, were willing to accept short-term treatment risks in exchange for longterm benefits, a significantly higher percentage of younger than older patients were willing to do so.Only 44% of patients, regardless of age, were willing to accept more longterm treatment risks in exchange for long-term benefits.Due to the substantial burden of cHL treatment, patients often face treatment decision trade-offs in which they must balance survival outcomes and side effect profiles.Concerns reported by more than 20% of patients include second cancers, heart disease and stroke, lung damage, infections and fertility issues, highlighting the importance of accounting for these side effects when selecting a treatment regimen.When compared with older patients, younger patients were more concerned about the risks of developing second cancers and the impact of treatment on fertility.Compared to younger patients, older patients were more concerned about lung damage and infection.
Results from a cross-sectional online survey that included a discrete choice experiment to investigate treatment preferences among 141 US participants with cHL showed that patients rated survival attributes as more important than drug-related toxicity when considering front-line treatments. 16The risk of progression at 2 years was of the highest relative importance (31.3%) to the surveyed participants when considering front-line treatment, followed by 2-year survival (26.9%), on-treatment pulmonary toxicity (23.3%) and on-treatment peripheral neuropathy (18.5%).
A survey carried out in Europe among patients with advanced cHL revealed that 5-year survival attributes were more important to patients than short-term adverse effects; however, pulmonary toxicity also remained a significant consideration. 15In a study based on semi-structured interviews with patients with HL in the United States (N = 17), the majority (71%) of patients said they wished they had learned about long-term treatment-related effects before initial treatment ended. 22Patients also discussed the impact of cancer on their lives, such as the effect on fertility.These data align with our findings from the CONNECT survey regarding the relative importance of stopping disease progression and prolonging survival while minimising treatment side effects.
Most patients in the CONNECT survey had a caregiver, and approximately one-third had a caregiver involved in treatment decisions, although the physician was given the most weight in terms of influence on treatment decisions.When the patient and caregiver surveys are viewed holistically, results show that patients and caregivers are highly aligned on treatment goals and that caregivers have a strong understanding of the cared-for patient's treatment goals.Data from patient-caregiver pairs show that 66% of pairs agreed on their top treatment goal, and for 94% of those who agreed, the top treatment goal was cure of cHL.These findings signal the importance of the patient's relationship not only with physicians but also with caregivers.Additionally, it is important to understand the relationships among patients, their caregivers and their physicians from all stakeholder viewpoints.[19]

Limitations
Results from the patient CONNECT survey may not be generalisable to all patients with cHL due to the method and nature of sampling by way of an opt-in group of survey participants and the need for participants to have the means to comfortably access an online platform.Additionally, approximately 64% of patients who participated in this survey were female, and 23% were non-White.Results may not be generalisable to the general cHL population, in which there is a higher incidence in males than females, and to populations that are more ethnically diverse.
All patients participating in this survey were from the United States.Drivers of patient treatment preferences may vary across other geographies, cultures and funding environments.This may be particularly relevant for geographic localities where escalated BEACOPP is a standard front-line therapy.In the United States, escalated BEACOPP is rarely administered frontline to patients with cHL due to its safety profile.
The impact of potential biases such as physician, financial and recall biases was not explored.Physician biases could have impacted both front-line therapy selection and patient responses related to treatment risks and goals.Financial biases could also have impacted front-line therapy selection, as front-line therapy selection could have been informed by insurance coverage.Recall could have biased our results, as patients were asked to recall symptoms at diagnosis and information from the time of treatment, which could have occurred 10 years prior to survey participation.Lastly, results from the paired patient-caregiver results may not be reflective of the larger sample, as there were relatively few pairs, and differences were noted in demographic and patient clinical characteristics between paired and non-paired caregivers.
While we acknowledge these limitations, with more than 180 patients diagnosed with stage III/IV cHL contributing to the survey, the CONNECT study, to our knowledge, is the largest survey of patients with cHL as of 2023.

F I G U R E 1
Symptoms experienced by patients prior to diagnosis of stage III/IV cHL that led them to seek medical attention.Patients were asked the following questions: What symptoms did you experience before you were diagnosed with cHL?Which of the symptoms you experienced led you to seek medical attention or treatment?Patients were asked to select all those that applied from the choices included in the figure.a Denotes a significant difference between patients aged <42 years and those aged ≥42 years.cHL, classic Hodgkin lymphoma.

F
I G U R E 2 Treatment preferences: goals for initial treatment.Patients were asked the following question: When thinking about initial classic Hodgkin lymphoma treatment, what are/were your top treatment goals?Responses shown reflect the percentage of patients who assigned a rank of 1 or 2 to the goal.a Denotes a significant difference between patients aged <42 years and those aged ≥42 years.