Previous studies have shown that cancer patients, across a range of subtypes, would choose to take medication as a daily, oral tablet over any other mode of administration when given the choice, primarily because of the ease and convenience [21,22,23,24]. Our study found the same trend, when patients were asked to choose between a daily, oral medication and a biweekly IV medication for treating their HCC, if efficacy and safety profiles were the same. However, when risks of AEs representing the safety profiles of the two currently available second-line treatments were introduced in a second direct-elicitation question, respondents often selected an IV administration with a safety profile similar to ramucirumab, rather than oral tablets with a safety profile similar to regorafenib.
To explain this shift in preferences between the two direct-elicitation questions, the level of each risk of AE included in the profile that exactly offsets the utility gained by having the preferred mode of administration was determined using the TT. Data from the TT show that for all the AE risks, most respondents who preferred oral tablets had a minimum reduction in risk needed to switch from tablets to IV infusion lower than the baseline reduction, except for ascites and peripheral edema. Similarly, when looking at respondents who preferred IV administration, for all the AEs, most respondents had a maximum increase in risk acceptable to keep IV infusion rather than switching to tablets lower than the baseline. All respondents in the IV series had a maximum increase in risk acceptable to keep IV infusion rather than switching to tablets that was lower than the baseline increase for the risk of diarrhea and hand-foot reaction. Similar shifts in preference from oral to IV administration when AEs are considered have been previously reported in patients with breast cancer and those with HCC [14, 21, 23]. A study of patients with HCC that compared preferences among available treatment options sorafenib, lenvatinib, and atezolizumab plus bevacizumab and SIR-Spheres found patients preferred therapies that provided them with lower risk of AEs over therapies that could prolong their lives by a few additional months [25].
Because ramucirumab is specifically indicated for patients with elevated AFP levels, we also examined the preferences of patients based on their AFP levels. As we saw with the main cohort, patients with elevated levels of AFP (> 400 ng/mL) preferred oral administration when the safety profiles were the same, but when risks were introduced, they preferred an IV treatment administered with a safety profile similar to ramucirumab. While this study was not able to discern a reason for this preference, other studies have shown that ramucirumab can prolong overall survival in patients with high AFP levels [4, 7, 26].
A major takeaway from this study and many like it is that maintaining quality of life by reducing AEs and using convenient modes of administration are of a high priority for many patients with HCC [25, 27, 28]. A recent study of patients with HCC indicates that patients are willing to make tradeoffs on convenience of dosing or even survival to avoid AEs and maintain their daily function [28]. Hypertension is consistently found to be an important AE to avoid for patients with HCC [27, 28], which is supported by our finding that the risk threshold estimates for which respondents were indifferent between tablets and IV infusion for hypertension was half the baseline risk, indicating that when considering hypertension as an AE, patients are willing to assume less risk than would be required for them to switch from IV to tablet. Understanding the preferences of patients with HCC with regards to their treatments is vital to providing the best possible medical guidance and healthcare. Recently, initiatives to gather patient perspectives and integrate patient preferences into their care have been gaining traction, including in life-sustaining treatment decisions [27,28,29]. This study advances the field of preferences of patients with HCC by shedding light on how patients weigh AEs and modes of administration when making healthcare decisions.
A limitation of this study is that patients who participated may have characteristics and preferences that differ from the overall population of patients in the US who have metastatic HCC. Most notably, 45.3% of respondents to this survey were female, but HCC is 2–3 times more common in men than in women [1, 30]. Because this study recruited during the first 6 months of the COVID-19 pandemic, we were unable to exercise much control over the demographics of respondents while ensuring we gathered a sufficient patient sample. The effects of sociodemographic differences in cancer treatment preferences have not been well established, however, so it is unclear what impact this might have had on the results of this study. In addition, patients who chose to respond to the recruitment invitation may have preferences that differ from those who chose not to respond to the recruitment invitation. While studies have indicated that survey-based studies generally agree with population-based studies, the potential for selection bias among this study cohort is possible [31]. However, data collected on patient demographics and clinical characteristics in this study do indicate that we captured data from a diverse sample, with patients from all residential regions, and with all forms of health insurance, methods of traveling to oncologists, and commute times (Additional file 1, Table S1). This study also evaluated only two HCC second-line therapies on the market and cannot, therefore, measure the degree to which additional available options may impact patients’ decisions in choosing a second-line therapy. However, other available tyrosine kinase inhibitors approved for treatment of HCC have similarly high rates of AEs; over two-thirds of patients treated with regorafenib, lenvatinib, or cabozantinib experience grade 3 or higher AEs [32]. Regorafenib and cabozantinib, two second-line tyrosine kinase inhibitors, have very similar efficacy and mode of administration as well [5, 8, 33, 34]. At the time this study was developed, cabozantinib was not available; however, it appears that some of the findings in this study could be applied to cabozantinib as well because of its similarity to regorafenib. While some studies indirectly comparing the efficacy of regorafenib and ramucirumab have been published since our study was conducted [35], of greatest interest to our study was the risk threshold that was acceptable to patients before switching between two drugs. Therefore, our study was designed to hold the efficacy of these two drugs constant throughout the survey questions. Finally, the data collected using the TT are based on responses to hypothetical choice profiles. These choices are intended to simulate possible treatment decisions but do not have the same clinical, financial, or emotional consequences of real-world decisions. Thus, differences can arise between stated and actual choices. We attempted to limit potential hypothetical bias by constructing choice questions that mimicked realistic clinical choices as closely as possible and mapped clearly into clinical evidence.
This study was performed as a hypothetical exercise for patients who may or may not have had experience with the drug administration routes in question. While this study is valuable as an illustration of how patients weigh the risks and benefits of certain medicines and routes of administration, future studies may also wish to examine the satisfaction of patients who are given choices of this nature when determining their own treatments in the clinic. It would also be interesting in future studies to measure the impact of quality of life on treatment preferences.