Patients with cancer experience disease and treatment-related symptoms that profoundly impact their quality of life and ability to function.1 Symptoms are further aggravated by newer cancer treatments such as immunotherapies that interfere with the immune system. With this disruption in immune balance, a unique set of toxicities referred to as immune-related adverse events has emerged. These events are classically autoimmune in nature and are often T-cell mediated.2

Toxic effects associated with immunotherapy are generally assessed via tabulation of adverse events, which are graded by clinicians. However, it is generally accepted that clinicians typically underestimate the symptoms of toxicity in patients under their care.3 To more accurately assess such symptoms, a better strategy is to rely on patient-reported outcomes (PRO). The patient symptom experience that is captured through PRO questionnaires administered during oncological clinical trials plays a critical role in how drug-approval agencies such as the US Food and Drug Administration and European Medicines Agency evaluate the overall clinical risks and benefits of new therapeutic agents.

Symptom assessment requires psychometrically validated tools that are easy to use and quick to administer. One such tool, the MD Anderson Symptom Inventory (MDASI),4 was designed to assess the severity of common cancer-related and treatment-related symptoms in a way that better reflects the symptom experience of the patient population with cancer. The MDASI assesses not only the intensity of cancer-related symptoms but also the level of symptom interference with daily functioning. Symptoms specific to a particular cancer, treatment method, or treatment site can be added to the core MDASI. In fact, we have done so, creating MDASI modules that include the 13 symptom and 6 interference items of the core MDASI augmented by additional disease-specific and treatment-specific symptom items. Specifically, we developed MDASI modules for patients with brain tumors,5 head and neck cancer,6 treatment-related heart failure,7 lung cancer,8 and malignant pleural mesothelioma,9 among others. The number of additional module-specific symptom items is minimized to keep the MDASI concise and easy to use in clinical and research settings and to facilitate repeated measurement.

The goal of the present prospective study was to demonstrate the reliability and validity of a MDASI module specific to immunotherapy for early-phase trials (MDASI-Immunotherapy EPT). This module asks patients to describe symptoms related to cancer in general and rate symptoms related specifically to immunotherapy during early-phase trials. We hypothesized that the MDASI-Immunotherapy EPT is a valid and reliable symptom assessment measure.

The MDASI-Immunotherapy EPT was developed to fill a need for an instrument that covered the spectrum of symptomatic adverse events that could be experienced by patients receiving immunotherapy. Although some other PRO measures have been used in immunotherapy, the MDASI-Immunotherapy EPT has several benefits and key advantages, such as that it is based on the core-MDASI that has been validated across cancer types and cancer treatments and available in multiple different languages. The MDASI-Immunotherapy EPT also has all eight symptoms that King-Kallimanis et al have described as critical adverse events related to immunotherapy, namely, fatigue, diarrhea, cough, shortness of breath, musculoskeletal pain, rash, pruritus, and fever.10 In their review of 28 registration trials for FDA-approved anti-programmed-cell-death-1 inhibitors, King-Kallimanis et al reported that 75% of these trials included PRO measures, and most trials used the EuroQol five dimension or the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire. King-Kallimanis et al indicated that no PRO measure reviewed included all eight symptoms that the authors considered as critical adverse events related to immunotherapy, namely fatigue, diarrhea, cough, shortness of breath, musculoskeletal pain, rash, pruritus, and fever.10 We note that all of these eight symptoms are included in the MDASI-Immunotherapy EPT.

Subjects were recruited from the Investigational Cancer Therapeutics department at The University of Texas MD Anderson Cancer Center. To be eligible for this study, individuals were required to be at least 18 years old, speak English, have a pathological diagnosis of cancer, and be receiving immunotherapy. Patients were excluded if clinical research staff felt that the patient was unable to understand or unwilling to sign a written informed consent document. Patients completed the MDASI-Immunotherapy EPT at baseline (before the initiation of immunotherapy) and after 9 weeks of treatment. All patients provided written consent to participate. This study was approved by the MD Anderson Institutional Review Board (protocol PA15-0315).

Of the 145 patients who completed the MDASI-Immunotherapy EPT at baseline, 85 also did so at week 9 of treatment. The reduction in the number of patients completing questionnaires at week 9 compared with baseline were due to attrition, or patients having come off the study due to progressive disease, clinical progression, withdrawal of consent or due to toxicities. The mean (±SD) patient age was 57.0±12.9 years. About 56% of the patients were women, 79% identified as white, and 49% had at least some college education. The five most common cancer diagnoses were colorectal (9%), skin (non-melanoma) (9%), ovarian (8%), cervix (7%), and sarcoma (6%).

In this study, we tested the immunotherapy-specific module of the MDASI in patients receiving cancer treatment in an early-phase setting. It is critically important to understand the symptomatic toxicity of cancer therapies in the early-phase setting. The results provide strong psychometric evidence for the use of the MDASI-Immunotherapy EPT. The module’s severity and interference subscales exhibited high internal consistency reliability. These two subscales also exhibited excellent known-group validity at week 9 as evidenced by substantial differences in MDASI-Immunotherapy EPT ratings based on ECOG PS groupings. MDASI-Immunotherapy EPT items such as difficulty remembering, fever and/or chills, disturbed sleep, diarrhea, and swelling of hands, legs, or feet exhibited high sensitivity to changes in ECOG PS.

The MDASI modules offer advantages over other symptom-assessment measures. First, unlike with disease-specific symptom scales, data collected using MDASI modules can be used to compare symptom prevalence and severity across cancer types, which is necessary for epidemiological studies and clinical trials that may include patients with different types of cancer. By rank-ordering the severity of core symptom items for different types of cancer, researchers can identify most of the symptoms that are consistently burdensome for patients with cancer and thus compare symptom burdens across cancers. A similar argument can be made for different cancer treatments where symptom burden due to hematopoietic stem cell transplantation can be compared with immunotherapy. Second, because validation of any symptom assessment measure is costly and requires time and effort, each validation of an MDASI module provides incremental evidence of the validity, reliability, and sensitivity of the original MDASI instrument. The core items can be included in new modules with fewer of the expected psychometric steps typically used in instrument development with the exception of demonstration that the core items are relevant and sensitive to changes in the target patient group. Third, the MDASI is available in several linguistically and psychometrically validated foreign language versions. A study of symptom ratings made by patients with cancer in four countries using four different language versions of the MDASI16 provided evidence of minimal variations in MDASI symptom ratings due to culture and language.

The ability of a PRO instrument to detect change was one of the criteria set forth in the US Food and Drug Administration’s guidance on the use of PRO in labeling claims. In particular, regulatory agencies are interested to see whether changes in the PRO scores are related to changes in patients’ state of functioning. We show herein that the MDASI-Immunotherapy EPT items are sensitive to changes in ECOG PS (related to disease). Furthermore, a recent study demonstrated that MDASI symptom items, such as coughing, fatigue, and shortness of breath, were predictive of survival in patients with lung cancer.17 Another study showed that fatigue, distress/feeling upset, and sadness were significant predictors of how symptoms interfered with daily functioning.18 These studies further establish the ability of the MDASI symptom items to detect changes in a patient’s status.

Our study was limited in that most of the subjects were from a comprehensive cancer center. Therefore, they may not be representative of cancer patients in general. However, our study also had the strength of a fairly large sample of patients receiving immunotherapy alone or in combination with other cancer therapies.

Future research involving the MDASI-Immunotherapy EPT should include at least three directions. First, we developed this module of the MDASI primarily by reviewing the literature and seeking input from clinicians. However, regulatory agencies, particularly the US Food and Drug Administration, recommend incorporating extensive patient input via qualitative interviews in developing symptom assessment tools, especially if a labeling claim is desired. Hence, qualitative patient interviews are needed to confirm the content validity of the symptom items in the MDASI-Immunotherapy EPT. Second, identifying what constitutes meaningful change is needed to facilitate the interpretation of MDASI-Immunotherapy EPT scores. Ideally, an anchor-based approach with several clinical anchors should be considered, complemented by the distribution-based method of determining meaningful changes in the scores. Finally, different immunotherapies may produce different toxicities and that requires further work. For instance, the chimeric antigen receptor T-cell therapy is associated with possible side effects that include cytokine release syndrome and neurologic problems.

The MDASI-Immunotherapy EPT is a valid and reliable instrument for assessing the severity of symptoms and their interference with function in patients with cancer receiving immunotherapy. As more immunotherapy combinations become available, future analysis might include using immunotherapy combination type in the subgroup analyses.