Prioritizing Chinese medicine clinical research questions in cancer palliative care from patient and caregiver perspectives

Abstract Background Chinese medicine (CM) modalities, including acupuncture and Chinese herbal medicine (CHM), are popular palliative interventions among patients with cancer, but further clinical research is required to assess their effectiveness and safety. Objective To prioritize top ten important CM clinical research questions from patients with cancer, cancer survivors and caregivers’ perspectives via a face‐to‐face prioritization workshop in Hong Kong. Methods A list of 25 CM clinical research questions for cancer palliative care, which were identified from existing systematic reviews (SRs) and overview of SRs, was presented to 17 participants (patients with cancer [n = 5], cancer survivors [n = 6] and caregivers [n = 6]). The participants were then invited to establish consensus on prioritizing top ten research questions. Results Among the top ten priorities, five (50%) focused on acupuncture and related therapies, while five (50%) were on CHM. The three most important research priorities were (i) manual acupuncture plus opioids for relieving pain; (ii) CHM for improving quality of life among patients receiving chemotherapy; and (iii) concurrent use of CHM plus loperamide for reducing stomatitis. Conclusion The top ten participant‐endorsed CM clinical research priorities for cancer palliative care can guide local researchers on future direction. They can also inform local research funders on patient‐centred allocation of limited funding. Under limited research funding, the most important co‐prioritized research question from professional and patient perspectives may be addressed first. Patient or Public Contribution Patients with cancer, cancer survivors and caregivers participated in conduct of the study to prioritize CM clinical research questions.


| INTRODUC TI ON
Cancer is a major contributor to global burden of non-communicable diseases. The World Health Organization estimates that by 2040, there will be nearly 29.5 million new cancer cases and 16.5 million cancer deaths worldwide. 1 With growing cancer incidence and advancement in cancer treatment, demand for palliative care among patients with cancer remains high in the past decades. 2 Palliative care refers to holistic care that enhances quality of life of patients and caregivers who face challenges associated with life-threatening diseases. 3 The US National Comprehensive Cancer Network (NCCN) recommends that palliative care should be offered to patients with cancer across the entire course of disease. 4 Patients receiving cancer palliative care often experience symptoms, such as pain, fatigue, nausea and vomiting. 5 Effectiveness of conventional pharmacological treatments for controlling these symptoms is limited, and some are associated with adverse effects. 6 Chinese medicine is a major form of traditional, complementary and integrative medicine (TCIM), which is extensively used as an adjunctive intervention for cancer palliative care. 7,8 In Hong Kong, more than 50% of patients with cancer have consumed at least one form of Chinese medicine modalities to reduce side-effects of conventional treatments, restrain tumour progression and improve quality of life. 9 Chinese herbal medicine (CHM) was the most commonly used Chinese medicine modality. 9 Findings of existing systematic reviews (SRs) 10,11 and overview of SRs 12-14 also indicated that CHM and acupuncture and related therapies are effective in relieving pain, fatigue, constipation and improving quality of life among patients with cancer. Nonetheless, in certain areas their effectiveness remains to be uncertain due to methodological flaws among existing studies. [10][11][12][13][14] Further clinical research should be conducted to ascertain their effectiveness.
With limited research funding for TCIM, there is an acute need in increasing research value of future clinical trials, as well as in avoiding duplication of effort and wastage of funding. Grant agencies should consider carefully what is already known or being researched currently, 15 as well as expectations from health-care professionals, patients and caregivers. 15,16 Prior to research priority setting, updated research evidence on Chinese medicine modalities for cancer palliative care should be systematically reviewed, and subsequently, knowledge gaps among current studies could be identified. 15,17 These gaps can then be translated to a preliminary list of clinical research questions for prioritization.
Research questions identified using the streamlined approach described above utilize existing evidence as a starting point in prioritization. This will facilitate allocation of limited research funding to confirmatory clinical trials since the priorities to be generated would have certain evidence support already. Arguably, this approach would bring the prioritization process closer to practice changes, as confirmatory trials are more likely to inform future clinical practice and guideline development. 18 In our previous international Delphi survey, 19 conventional physicians, Chinese medicine practitioners, nurses and clinical research methodologists prioritized eight research questions from a preliminary list generated from existing clinical evidence. However, the needs of patients with cancer, cancer survivors and caregivers in this field remain uncertain. This study aimed to prioritize top ten important Chinese medicine clinical research questions in cancer palliative care from their perspectives via a face-to-face prioritization workshop in Hong Kong. The identified potential research needs were then presented clearly using the PICO (patients, interventions, comparisons and outcomes) framework, along with the methodological limitations of existing studies (see Appendix S1). Thirdly, we converted these research needs to preliminary clinical research questions, which incorporated the PICO elements. Lastly, content of these potential research questions was amended based on comments from caregivers of patients with cancer and Chinese medicine practitioners specializing in oncology. Such amendment was to ensure that our study participants would be able to comprehend the research questions. Accordingly, a list of 25 Chinese medicine clinical research questions for cancer palliative care was prepared for prioritization in a face-to-face workshop (see Appendix S2).

| Part 3: Data collection and analysis
Eighteen participants, including patients with cancer (n = 6), cancer survivors (n = 6) and caregivers (n = 6), were invited to a face-to-face prioritization workshop held on 1 June 2019. Participants were informed about the study's purpose, confidentiality of their personal information and that their participation was voluntary. Participants who agreed to join were asked to sign a written informed consent before the workshop began. Two rounds of small group discussion in the workshop were facilitated by research team members (CHLW, WW and VCHC) who were experienced in qualitative research. The workshop was comprised of five phases (Figure 1). F I G U R E 1 Details of the face-to-face workshop Phase 1: Individual ranking -Participants (n=18) were asked to rank priority of a preliminary list of 25 research questions individually Phase 2: Round 1 small group discussion and ranking -Participants were split into three small groups -Participants were invited to give comments and rank a list of top ten research questions based on their importance via the small group discussion Phase 3: Whole group review -Round 1 ranking scores from each group were summed up -Research questions with the top ten highest ranking scores were extracted for discussion in the next phase Phase 4: Round 2 small group discussion and ranking -Participants were re-arranged to three new small groups -The extracted list of research questions with the top ten highest sum of ranking scores in the first round was presented to each new group -Participants in each new group were asked to discuss and reexamine this list of questions, and re-rank the questions based on their importance if needed Phase 5: Final whole group review -Round 2 ranking scores from each new group were summed up -A list of research questions, with the top ten highest sum of ranking scores in the second round was presented to all participants -Ensure that the final ranking of the top ten questions was agreed among all participants -Finalize a list of top ten participants-endorsed important research priorities 1. In Phase 1, participants were asked to rank the priority of the list of 25 research questions prepared in part 1 individually (see Appendix S2).
2. In Phase 2, first round of small group discussion was conducted by dividing the participants into three groups (n = 6 in each group), with a balanced number of patients with cancer, cancer survivors and caregivers (n = 2 from each category). Each participant was invited to comment on research questions which they felt were the most, and the least, important for further research. Based on the discussion, they were then asked to select top ten important research questions out of the list of 25 research questions.
3. In Phase 3, for each group, research questions on the top ten list ranking from 4th to 10th were given 1 point, while questions ranking from 1st to 3rd were given 3 points. 22,23 Then, ranking scores of all three groups in the first round were summed up. 22,23 Based on the sum of ranking scores, research questions with top ten highest consensus ranking scores were extracted for discussion in the next phase. 22,23 4. In Phase 4, second round of small group discussion was conducted by re-arranging participants to three new groups. A list of research questions with the top ten highest sum of consensus ranking scores in the first round was presented to each new group.
Question with highest consensus ranking score was ranked as 1st, while question with lowest consensus ranking scores was ranked as 10th. Participants in each new group were asked to discuss and re-examine this list of questions, and re-rank the questions based on their perceived importance if needed. 22,23 5. In Phase 5, data analysis similar to Phase 3 was performed. A list of research questions, with top ten highest sum of consensus ranking scores in the second round, was presented to all participants.
Similar to Phase 4, the questions were arranged in a descending order, such that the question with the highest score sum were ranked as 1st. In areas where consensus was not established, agreements were reached by majority voting. 22,23 A finalized list of top ten participant-endorsed research priorities was generated at the end of workshop.

| Participants
Seventeen participants attended the face-to-face prioritization workshop (response rate: 94.4%), including patients with cancer who have completed major cancer treatment (n = 5), cancer survivors who have survived for five or more years after diagnosis (n = 6) and caregivers who have taken care of patients with cancer (n = 6).
Of these 17 participants, 58.8% of them were female and majority of them (82.4%) were aged 40 years or above. The duration of receiving Chinese medicine modalities for cancer palliative care among patients with cancer, cancer survivors and patients with cancer who were looked after by caregivers in this study ranged from 2 months to 102 months (see Appendix S3).

| Generation of top ten Chinese medicine clinical research priorities
From the workshop, top ten Chinese medicine clinical research priorities in cancer palliative care agreed by all participants are listed in Table 1. Details of participants' qualitative comments on these priorities are shown in Table 2. Among these ten research priorities, five (50%) focused on acupuncture and related therapies, while five (50%) were on CHM.
The three most important research priorities with highest ranking scores were as follows: 1. Combining manual acupuncture and opioids for relieving pain; 2. CHM for improving quality of life among patients who undergo chemotherapy; and 3. CHM plus loperamide for reducing stomatitis.
Manual acupuncture plus opioids for relieving pain among adult patients receiving cancer palliative care was considered the most important among these three research priorities. All study participants agreed that pain reduction should be a priority before managing other symptoms or improving quality of life. One caregiver indicated that persistent pain would have significant negative impact on physical and psychological health of patients with cancer. As described by one patient with cancer and two cancer survivors, the use of opioids on pain relief might induce serious side-effects, such as dizziness, extreme drowsiness, hallucinations and loss of coordination.
Another cancer survivor suggested that conventional physicians might consider reducing the dosage of opioid use if adding manual acupuncture is found to be effective in reducing pain in future studies ( Table 2).
The second-most important research priority was the use of CHM for improving quality of life among adult patients receiving cancer palliative care who undergo chemotherapy. From their personal experiences, one patient with cancer and one cancer survivor stated that using CHM was effective in improving their quality of life, and this was considered to be an important outcome among those receiving cancer palliative care. A cancer survivor highlighted that maintaining good quality of life was essential even after the completion of chemotherapy. One patient with cancer and one caregiver expressed conventional physicians' concerns on the potential risk of herb-drug interactions induced by combined administration of CHM and chemotherapy ( Table 2).
Concurrent use of CHM and loperamide for reducing stomatitis among adult patients receiving cancer palliative care was the thirdmost important research priority. One cancer survivor mentioned that her stomatitis during chemotherapy had prevented her from feeding normally. She was worried that inadequate nutrient intake would impede her ability to recover and subsequently led to other health problems. Two caregivers also highlighted that stomatitis led to severe pain on top of appetite loss. Personal experiences of a caregiver suggested that CHM was effective in relieving stomatitis of patients with cancer, and therefore, research is needed to confirm this observation (Table 2).

| Other qualitative comments and future research recommendations
Two caregivers indicated that research priorities should be varied for patients with cancer currently undergoing major cancer treatment, pre-treatment and post-treatment since the symptoms experienced by patients at different stage vary significantly. These caregivers also mentioned that symptom variations among patients with different cancer diagnoses were apparent. Therefore, separate research priority ranking based on patients' stage of treatments and cancer diagnoses should be considered in the future (Table 2).

| Summary of findings
In this study, patients with cancer, cancer survivors and caregiv-  Is adding manual acupuncture on top of conventional care more effective in reducing anxiety among adult patients receiving cancer palliative care?
10 Note: The final ranking was arranged in a descending order based on the sum of ranking scores. The research question with the highest ranking scores among these top ten important research priorities was ranked as 1st.
Abbreviation: CHM, Chinese herbal medicine. Without essential nutrients to nourish, repair, and heal our body, we are highly vulnerable to different health problems. The role of CHM needs urgent evaluation. Caregiver: • Stomatitis not only results in appetite loss, but also brings severe pain. • My mother suffered from stomatitis after undergoing chemotherapy and radiotherapy. She could not swallow anything at that time because of the severe pain caused by stomatitis. We relied on the use of CHM to reduce stomatitis and improve her overall health conditions, so I think this is an important research question. • During chemotherapy, stomatitis would result in anorexia and patients cannot eat anything.
As we mentioned that anorexia is undesirable. If CHM is capable of treating stomatitis, anorexia will also be reduced. (Continues)

Research questions Final ranking Qualitative comments
Is adding CHM on top of conventional care (granulocyte colony-stimulating factor (G-CSF)/granulocyte-macrophage colony-stimulating factor (GM-CSF)/ interleukin-3 (IL-3)) more effective in improving leukopenia among adult patients receiving cancer palliative care?
4 Patient with cancer: • I noticed that the use of CHM alone was effective in improving leukopenia among some patients with cancer. These patients didn't need to receive G-CSF injection. Research is needed to prove my observation. Cancer survivor: • I got mild fever and severe bone pain after G-CSF injection. Its side-effects made me feel even more uncomfortable than receiving chemotherapy. Hence, it is important to investigate an alternative approach like CHM to improve leukopenia. We may then reduce usage of G-CSF injection. • Even I had good appetite when receiving chemotherapy, it was still difficult to maintain white blood cell count at a normal level. I think it is very important to research the potential of CHM for improving leukopenia among patients receiving cancer palliative care, especially during or after chemotherapy. Caregiver: • If the combined use of CHM and G-CSF is effective in normalizing white blood cell level, patients with cancer may not need to delay their chemotherapy treatments. Hence, I think this research question is important.

| Mismatches on perceived research priorities between experts and patients
This face-to-face prioritization workshop shared a similar approach with our previous international Delphi survey 19  Grant agencies might consider addressing these three co-prioritized questions as priorities.

| Strengths and limitations of this study
In this workshop, patients and caregivers from diverse background could express their expectations via structured interactions.
Through ranking exercise within the small group discussions, every participant's viewpoints could be considered. 22,23 The domination of discussion by a single participant was also prevented. 22,23 Besides, patients and caregivers could feel empowered by making contributions to prioritizing research questions. 43 Future research needs may be identified from knowledge gaps on other Chinese medicine interventions, such as tai chi 44 and cupping therapy. 45 Our research priorities were generated among local participants who have experiences of using Chinese medicine modalities for cancer palliative care. Hence, findings might not be directly generalizable to other health system context and culture. Our study participants were not categorized according to patients' stage of treatments and cancer diagnoses. Nevertheless, our findings were agreed by all participants. These prioritized research questions remain to be highly relevant regardless of cancer stage and severity.

| CON CLUS ION
We prioritized a list of top ten important Chinese medicine clinical research questions for cancer palliative care among patients with cancer, cancer survivors and caregivers in Hong Kong. These priorities will guide clinical researchers on future direction and will inform grant agencies on rational allocation of limited funding. To maximize research value and minimize wastage of funding, it is important to align the priorities from both professional and patient perspectives.
The most important co-prioritized research question may be addressed first with appropriate support in the near future.

ACK N OWLED G EM ENTS
The authors are grateful to all patients with cancer, cancer survivors and caregivers who participated in this study for offering illuminating insights.

CO N FLI C T O F I NTE R E S T
None.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.