Patient-Reported Outcomes of Pain and Related Symptoms in Integrative Oncology Practice and Clinical Research: Evidence and Recommendations

Oncology (Williston Park). 2021;35(1):35-41.
DOI: 10.46883/ONC.2021.3501.0035

Introduction

Currently, there are approximately 17 million cancer survivors in the United States. This number is projected to increase to 22 million by 2030 due to dramatic decreases in mortality secondary to novel anticancer therapies.¹ In addition, the American Cancer Society estimates that approximately 1.8 million people will be newly diagnosed with cancer in 2020.² Patients with cancer are at significant risk for chronic physical and psychological symptoms.³ Despite cancer treatment advancements and multidisciplinary approaches, cancer pain remains a common and challenging issue affecting up to 66% of patients with cancer.^4-7 Furthermore, cancer pain management is often suboptimal due to patients’ vulnerability, their reluctance to report pain, communication challenges with their care team, and health barriers and disparities.^8-10

Oncology clinicians use pharmacologic and nonpharmacologic interventions to manage cancer-related pain. Commonly used conventional treatments include opioids, anticonvulsants, muscle relaxants, and topical or local injections; however, these are often expensive and associated with adverse events (AEs). Nonpharmacologic integrative oncology interventions include acupuncture, massage therapy, music therapy, yoga, meditation, tai chi, qigong, and nutrition and lifestyle changes, among others. Evidence suggests that these therapies can effectively alleviate cancer pain and associated symptoms while improving quality of life (QOL), with relatively low cost and fewer AEs than pharmacologic agents (with the exception of some over-the-counter medications such as acetaminophen or ibuprofen, which can have serious AEs).^11-13

Consequently, many professional societies, regulatory bodies, and governments now recommend that comprehensive, evidence-based, patient-centered pain management approaches include nonpharmacologic treatment options. The 2016 CDC guidelines recommend nonopioid therapy as the preferred management strategy for chronic pain.¹⁴ Both the American Society of Clinical Oncology (ASCO) clinical practice guideline and the National Comprehensive Cancer Network guideline recommend nonpharmacologic interventions, including acupuncture and massage, to treat cancer pain alongside conventional care.^15,16 Since 2018, the Joint Commission has also required nonpharmacologic modalities for pain management.¹⁷

Accurately assessing patients’ symptoms, the impact of symptoms on QOL, and response to treatment are critical factors for improving patient outcomes, care quality assurance, and clinical research. To guide industry in including patient-reported outcomes (PROs) in medical product development, the Food and Drug Administration (FDA) defined PROs in 2009 as “any report of the status of a patient’s health condition that comes directly from the patient, without interpretation of the patient’s response by a clinician or anyone else.”¹⁸ PROs can be collected by written questionnaires, in-person interviews, phone conversations, and digital technology. Well-defined and reliable PROs have been shown to improve patient satisfaction and symptom control in patients with and without cancer.¹⁹ Pain PROs can also be used to study patient-physician communication outcomes, patient compliance and satisfaction, and quality improvement and performance measures. In addition, results of PROs provide evidence that may impact regulatory decisions.20 However, while PROs are useful for patient assessment, the lack of coherent practices creates challenges in utilizing and interpreting
them effectively.

The Society for Integrative Oncology (SIO) promotes rigorous, evidence-based, comprehensive complementary approaches to cancer care. In this article, we review and summarize evidence for commonly used cancer pain PROs in the setting of acute and chronic cancer pain and discuss implications for their use in routine integrative oncology care and clinical research. Our primary focus is on providing guidance for how to use PROs to evaluate chronic cancer pain, bone metastases–related pain, and acute pain after oncological surgery or interventions. Patients with chemotherapy-induced peripheral neuropathy (CIPN) often experience neuropathic pain in their hands and feet, along with numbness, tingling, and other symptoms such as weakness and dysfunction that disrupt their daily activities. While painful neuropathy is an important symptom, multiple validated neuropathy-specific PROs to characterize neuropathic pain and neuropathy severity already exist.^21-23 Thus, PROs to assess CIPN is beyond the scope of this review and will not be discussed in detail.

Cancer Pain Patient-Reported Outcome Measures

Cancer pain PRO measures should be reliable, validated, and easy for providers, patients, and investigators to use. They may be qualitative or quantitative, or include both elements. Quantitative measures include pain intensity, severity, and impact, while qualitative pain PROs usually include evaluation of pain quality, history, alleviating or aggravating factors, and pain expectation. See the Table for a summary of the current most commonly used cancer pain PROs.

TABLE. Summary of Validated Quantitative and Qualitative Patient-Reported Pain Assessment Instruments

Pain Intensity Assessments

The most commonly used quantitative pain PRO is pain intensity. This assessment is straightforward and cost-effective, while minimizing bias from health care professionals. Patient-reported pain intensity objectively measures pain severity and impact on QOL, as well as indications for intervention. The most commonly used methods for determining patient-reported pain intensity are numerical rating scales (NRS), verbal descriptor scales (VDS), and visual analogue scales (VAS). NRS, VDS, and VAS are highly intercorrelated and reliable.²⁴ NRS are more reliable than VAS in clinical trials, especially among patients with low socioeconomic status.²⁵

Numerical rating scales have been validated in clinical and research settings as standard pain measures. One of commonly used NRS,the Brief Pain Inventory (BPI) uses an 11-point pain intensity scale ranging from 0 (“no pain”) to 10 (“worst pain imaginable”); it is among the most widely used NRS pain scales developed specifically for patients with cancer-related pain.²⁶ It is a validated measure of pain intensity and is sensitive to changes over time.^27,28 Patients can rate their pain as “right now,” “average,” “at its least in the past 24 hours,” and “at its worst in the past 24 hours.” Furthermore, the BPI provides information on how pain interferes with daily functioning in 7 aspects: general activity, walking, mood, sleep, work, pleasures in life, and social activity. The BPI is highly reproducible and results are comparable between patient self-administration and interviewer administration. In a study conducted by ECOG, the BPI was used to determine the prevalence and severity of cancer pain among 1261 patients with cancer from 80 cancer centers in the United States.²⁹ The investigators demonstrated that the BPI was highly consistent with other pain measures and interference factors associated with pain intensity.³⁰ The BPI has a few additional advantages compared with other pain assessment tools: It is brief (can be completed within 5 minutes), can be self-administered by the patient, can be completed remotely by phone or via telemedicine, and is available in multiple languages.^31,32

Verbal descriptor scales (VDS) and verbal rating scales (VRS) ask patients to categorize their pain intensity as “none,” “mild,” “moderate,” or “severe.”^33,34 Patients self-define these categories; they can be highly variable due to factors such as age, gender, race/ethnicity, language, and culture.³⁵

Visual analogue scales (VAS) determine pain severity by asking patients to indicate a position along a continuous line between 2 end points, one end representing “no pain” and the opposite end representing “worst pain imaginable.”^36,37 However, there are some issues with VAS, such as patients often drawing a line in the middle. While VAS has been proven useful in clinical and research settings, it may be difficult for some patients to comprehend.²⁵

Pain Relief and Patient Satisfaction Scales

Pain relief and patient satisfaction scales are important tools for evaluating PROs and response to treatment. They can be administered at different time points to provide information regarding the immediate and long-term effects of a pain intervention.

The pain relief scale (PRS) measures changes in pain intensity over a period of time.³⁸ Patients are asked to rate their pain intensity changes on a scale that includes “worse,” “the same,” or “complete relief.” The PRS may be useful for capturing response shifts in longitudinal pain assessment.³⁹ However, the most popular measurement of pain reduction has been the pain score change with repeated assessment of pain severity.

The Patient Satisfaction Scale (PSS) asks patients to rate their satisfaction with their current pain management on a scale of 1 (“very dissatisfied”) to 5 (“very satisfied”).⁴⁰ This scale reflects patient preferences for and expectation of pain relief and is commonly used in pain management quality reassurance.⁴¹ Results may be misleading, as evidence suggests that patients will rate their satisfaction levels as high despite having moderate-to-severe pain.⁴² As such, results from the PSS should be carefully interpreted with consideration for patient preferences, expectations, their confidence in providers, presence of adequate social support, and history of depression.⁴²

Other Patient-Reported Putcome Measures for Cancer-Related Pain

The Pain Interference Scale is part of the BPI and measures the impact of pain on functional status. It has been validated in many diseases and acute or chronic pain conditions, including bone metastases and cancer-related neuropathy, and has been found reliable and sensitive to treatment dose response.^43-45

The Patient-Reported Outcome–Common Terminology Criteria for Adverse Events (PRO-CTCAE) measurement system includes cancer pain as an important symptom toxicity measure and was developed based on the Common Terminology Criteria for Adverse Events in cancer clinical trials by the National Cancer Institute. It assesses pain frequency, severity, interference, and attributes. PRO-CTCAE can be implemented electronically and has been validated in more than 30 languages. It has demonstrated acceptable validity and reliability.^46-48

Health-related quality-of-life (HRQOL) measures include the Short-Form 36 questionnaire, the European Organization for Research and Treatment for Cancer Quality-of-Life questionnaire, the Functional Assessment of Cancer Therapy, and the Patient-Reported Outcomes Measure Information System. These forms often include pain as a subscale and have been incorporated in many pain trials to assess the effects of an intervention on HRQOL.^49,50 HRQOL evaluates 4 dimensions: physical function, psychological function, social function, and symptoms related to disease or treatment. In cancer patients, pain severity is negatively associated with HRQOL. Among those with moderate-to-severe pain, HRQOL was significantly decreased compared with patients without pain or with only mild pain.⁵¹ Both ASCO and the FDA recommend HRQOL as an important end point in cancer patients secondary to survival.^18,20,50

Symptom burden measures evaluate the symptoms associated with cancer pain such as fatigue, anxiety, insomnia, and anorexia. These measures are designed to capture multiple symptoms and often include assessment of pain and pain treatments (eg, opioids) associated with multiple symptoms. These features can be used to guide pain management. The most commonly used validated, reliable scales are the Symptoms Distress Scale (SDS), the Memorial Symptoms Assessment Scale (MSAS), the MD Anderson Symptom Inventory (MDASI), and the Edmonton Symptom Assessment System (ESAS).52-56 It is important to note that increasing pain severity is often associated with increasing symptom burden, but that the relationship is not necessarily linear. Symptom burden measures can be incorporated to determine pain severity and a treatment plan.

Electronic PROs (ePROs) Assessment

Electronic medical record (EMR) systems and the widespread use of electronic devices such as computers and smartphones have promoted interest in electronic PROs assessment (ePROs). With ePROs, patients can report their pain symptoms and HRQOL-related dysfunctions via a digital web-based interface, such as a smartphone application (app), a website, or an automated phone system that allows for flexibility in collecting and analyzing PROs data. ePROs data can be directly stored and integrated into the EMR so that the health care team can evaluate a patient’s responses in real time as well as conduct a longitudinal review. It can also generate e-notifications/alerts based on predefined criteria to notify a patient’s health care team immediately and prompt necessary actions.

Results from randomized controlled trials demonstrate improvements in QOL and overall survival by incorporating ePROs into oncology care. For example, using MDASI via an automated phone system significantly reduced pain after thoracic surgery and other symptoms in lung cancer patients.⁵⁷ In a randomized controlled clinical trial, Denis et al showed improvement in overall survival in early-stage lung cancer patients using web-based ePROs.⁵⁸ During the recent coronavirus disease 2019 (COVID-19) pandemic, telemedicine has been adapted quickly to continue clinical care while minimizing the risk of COVID-19 exposure.^59,60 ePROs could have a unique advantage in this setting if health care providers utilize them for remote monitoring of symptoms to facilitate communication between patients and their care teams. They may also be used as early interventions to reduce emergency department visits and hospital stays.

Application of Pain PROs in Integrative Oncology Clinical Research

Integrative approaches to pain relief such as acupuncture, massage, yoga, qigong, tai chi, and meditation require frequent symptom assessment. Standardized, cancer-specific pain PROs can be used to assess pain severity, intensity, pain interferences, satisfaction, and HRQOL during the treatment course. Collection of PROs at multiple time points, including before and after treatment, allow for the capture of longitudinal information to guide appropriate intervention. Assessments should be validated, sensitive, and easy to administer and interpret. To define pain severity, health care providers and investigators should use validated and reliable measures that categorize pain, such as the BPI. To measure pain relief effects, they can incorporate pain relief scales or patient satisfaction scales. Other outcomes such as pain interference, HRQOL, MDASI, ESAS, or MSAS enhance comprehensive pain assessment in addition to pain intensity, and they include symptoms associated with pain, QOL, and patient satisfaction with pain relief. While multiple PROs can be utilized simultaneously, a mixed model of evaluation may lead to heterogeneous results that are difficult to interpret. Respondent burden is also a consideration. Thus, providers and investigators must identify the specific clinical issue of interest and select the most appropriate PROs that align with the intervention.

Multiple working groups have made enormous efforts to address the methodological issues in study design and interpretation of results associated with utilizing PROs in clinical trials.^61-64 When designing a clinical trial to evaluate the effectiveness of integrative interventions to treat cancer pain, substantial differences in reporting outcomes from using a combination of scales can cause confusion in the interpretation and generalizability of research findings.

Careful selection of the most appropriate PROs is essential for the conduct of a successful clinical trial. It is important to consider the following key elements: First, identify the specific population for the intervention of interest. For example, certain pain characteristics, such as bone pain related to metastases or acute postprocedure pain, may respond to acupuncture or massage differently. Thus, clearly defining the target population—for example, cancer survivors with chronic pain or patients with active painful bone metastases—can increase homogeneity and limit confounding factors. Second, select the most appropriate primary or secondary end points such as pain intensity, HRQOL, analgesic reduction, or symptom burden associated with pain. The selected end points should be based on a carefully developed hypothesis and potential outcomes of interest (eg, the MDASI burden questionnaire for a study of music therapy for reduction of cancer pain-associated symptoms, or an NRS scale to measure pain intensity for a study of acupuncture for acute bone metastases pain). Third, create a rigorous study design and statistical analysis plan to calculate study sample size and expected PROs changes. Using the example above, an NRS reduction of 2 points or >20% has been correlated with minimal pain improvement in patients regardless of baseline pain severity.⁶⁵ Pain score reductions of less than 2 points may be statistically significant but might not be clinical meaningful, such as when the pain score remains mild (eg, 0-4/0-10) or severe (eg, 7-10/0-10). Therefore, it is important to observe the reduction in pain from moderate/severe to none/mild through an effective intervention. Fourth, the study should have a detailed plan for collecting PROs that is concise and easy for patients; it should include defined data collection time points, determination of whether data will be collected in-person or electronically (eg, phone, apps, or online surveys), and a data safety plan. Lastly, it is necessary to thoroughly plan for all possible pitfall scenarios, such as incomplete or missing data.

How to Interpret PROs Comparative Effectiveness Research in Integrative Oncology

Methodologies are unique to evaluate integrative oncology intervention clinical trials that often focus on symptom management and improving QOL. Survival benefit is less likely to be the primary goal. Thus, clinical trials evaluating integrative therapies must include patients’ perceptions of treatment expectancies, intervention effectiveness, AEs, and overall QOL. PROs are a valuable tool in comprehensive pain assessments, which can be inconsistent when based on grading assessments from providers and care teams.48 The ASCO Quality Care Committee and the National Quality Forum recently recognized the need for clearly defined PROs specific to cancer pain, particularly pain from bone metastases, and have prioritized establishing recommendations regarding their use.⁶⁶

Current guidelines and recommendations for the use of PROs in clinical research need to be adapted to meet the specific needs of integrative oncology research and practice. Efforts to increase awareness of robust clinical evidence surrounding the effectiveness of integrative interventions for cancer-related pain and enhance widespread utilization of these techniques are needed.⁶⁴ PROs are subjective; however, the evaluation of PROs must be scientifically sound. Readers must have full knowledge of existing evidence and gaps based on extant literature in the identified study population to properly interpret and understand clinical trial results and examine the study hypothesis. Further, since PROs are often multidimensional, it is important to clearly identify the PRO as the primary or secondary end point linked to the study hypothesis in order to determine its rationale and significance. The method of analysis in PRO research was adapted from therapeutic intervention trials, but because PROs are multidimensional and collected at multiple time points, statistical analyses are at risk of false positive results. Readers must be aware of this bias, particularly when the study reports positive results for multiple end points without providing detailed documentation of the statistical analysis plan. The study should also have a clearly defined statistical plan to handle missing data. Readers must exercise caution regarding the sensitivity and validity of PROs before accepting the results and applying them to daily practice and clinical research. Standardizing cancer-specific PROs will aid in study design and statistical planning in integrative oncology clinical trials so that researchers and providers can utilize novel findings in large-scale meta-analyses and quickly adapt them for clinical practice.

Barriers and Limitations of Pros in Integrative Oncology Research

Because pain is subjective in nature, using PROs to assess pain and pain-related symptoms provides important patient-centered feedback and serves as a platform for effective communication between patients and clinicians. Concurrently, PROs can be challenging because of their subjectivity. Patients may not be aware of the importance of PROs, which can lead to noncompliance with pain treatment regimens. The utility of PROs in the patient-centered care model may also lack linguistic validation and cultural adaption, causing reporting bias. However, based on international studies, well-validated tools in different languages have minimal negative impact on pain and other PROs.⁶⁷ Patient and advocate concerns about PROs should be effectively communicated with the clinical team and appropriate education materials and trainings should be provided for patients and their care partners.

With multiple validated PRO tools available, choosing the most suitable PRO can be overwhelming. For this reason, we have included a summary of validated cancer-related pain PRO instruments in the Table. Integrative oncology researchers and practitioners may use it to select appropriate pain-related PROs for their specific interests and needs.

Another major challenge is the implementation of PROs into clinical practice and research. Implementation involves training of physicians, nurses, and research staff, as well as providing clear instructions to patients; systemic—and ideally automatic—collection of PROs into EMRs; and adequate data storage. All of these factors can be labor-intensive and involve a sharp learning curve for those who are new to collecting PROs. Practitioners and researchers should also be mindful of the potential reporting burden for patients who may be expected to answer other symptom assessments in addition to those about pain. Guidance from government and support from institutional leadership can facilitate this process. Furthermore, the methodology used to analyze PROs is imperfect. Multidimensional and multiple time-point PROs collection can lead to statistical drawbacks and pitfalls.⁶⁴ Rigorous methodology development to overcome current challenges remains the priority in PRO research.

Conclusions and Recommendations

The SIO Research Committee strives to increase awareness of current national and societal guidelines and recommendations related to PROs to promote their adoption into clinical practice and research. Multiple validated and reliable PROs accurately assess pain and related symptoms in cancer patients and survivors. In integrative oncology practice, these PROs have essential value and should be incorporated routinely in clinical care.

Based on available evidence, we recommend the following commonly used PROs to assess cancer pain and related symptoms, alphabetically: BPI, ESAS, MDASI, MSAS, and PRO-CTCAE. These tools are essential to the integrative oncology care team and should be incorporated routinely into clinical practice. Electronic PROs provide flexibility in collecting and analyzing PRO data. Education regarding pain PRO tools should be extended to patients, caregivers, the entire cancer care team including physicians and nurses, the research team, and institutional leadership. Infrastructure to streamline PRO collection, data storage, and safety are also necessary for using PROs in daily practice.

The PROs described in this paper are vital for integrative therapy development, with the primary goal of reducing symptom burden and improving QOL in people affected by cancer. When studying the effectiveness of integrative inventions in cancer pain, PROs may be the primary or secondary end points with a specific hypothesis, clearly defined population, and detailed statistical plan. The FDA has put forth standard methods of applying PROs in clinical trials; researchers should apply these standards to pain intervention trials utilizing integrative techniques.¹⁸ Detailed strategies for PRO collection, data analysis, and handling missing data are key steps to success. Lastly, the timely publication of high-quality research findings will facilitate dissemination of information to ensure that clinical practice can be adjusted accordingly, and patient outcomes can be maximized.

With the increasing incidence and prevalence of cancer in the United States, accurate and frequent assessment of pain and pain-related symptoms is paramount. Validated PROs specific to cancer-related pain are essential tools in the armamentarium for clinical oncologists and researchers. It is imperative that clinicians understand the role of PROs, as well as their limitations, in both practice and research, so they can be used and interpreted effectively. As the number of integrative interventions for pain and related symptoms continue to increase, PROs will provide insight regarding the effectiveness of these interventions on both the individual and population levels. Use of PROs will lead to the expansion of current evidence-based practice guidelines for integrative oncology practitioners.

Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

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Zhi is an assistant attending in Breast Medicine Service, Solid Tumor Division, Memorial Sloan Kettering Cancer Center.

Gentile is a health services researcher senior and assistant professor of medicine, Department of Supportive Oncology, Levine Cancer Institute.

Diller is an assistant professor, Department of Surgery, Winship Cancer Institute, Emory University School of Medicine.

Kinney is a professor, Department of Biostatistics and Epidemiology, School of Public Health, and Rutgers Cancer Institute of New Jersey.

Bao is director, Integrative Breast Oncology, Integrative Medicine and Breast Medicine Services, Memorial Sloan Kettering Cancer Center.

Wang is a professor, Department of Symptom Research, The University of Texas MD Anderson Cancer Center.

Corresponding Author

W. Iris Zhi, MD, PhD

Breast Medicine Service, Solid Tumor Division

Memorial Sloan Kettering Cancer Center

650 Commack Road, Commack, NY 11725

Email: zhiw@mskcc.org

Telephone: 631-623-4246

Fax: 631-864-3942