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Page 8 of 14 Webster et al. J Cancer Metastasis Treat 2020;6:8 I http://dx.doi.org/10.20517/2394-4722.2019.38

Figure 3. Conceptual framework. PRO: patient-reported outcome; ICM: immune checkpoint modulators

blood in stool, and mouth sores); skin (rash, itch, dryness, cracking/peeling, blistering, vitiligo, sensitivity
to sun, and pain); lung (shortness of breath, cough, wheezing, and chest pain); neurologic (coordination
and balance); musculoskeletal (joint pain, joint stiffness, swelling, muscle weakness, and muscle pain); and
miscellaneous/constitutional (fatigue, headache, weight gain, weight loss, appetite, lightheaded/dizziness,
blurry vision, urinary frequency, fevers, chills, nervousness, palpitations, sweating, dry mouth, dry eyes,
sandy/gritty eyes, sinus pain, incidence of new allergies, and acute treatment reactions). Of the 66 items,
53 are primary and 13 supplemental [Table 1]. All symptoms are part of the larger FACIT Immunotherapy
Item Library.

Conceptual framework development
To inform our conceptual framework, we used recently issued guidelines for the identification and
management of immunotherapy-related toxicities from The American Society of Clinical Oncology,
in collaboration with the National Comprehensive Cancer Network, the European Society for Medical
Oncology, and the Society for Immunotherapy of Cancer Toxicity Management Working Group [9,10,39] .
Collectively, these guidelines identify primary ICM-related immune conditions by organ system,
highlighting key symptoms for each, which we then used as the organizing conceptual structure of our
immunotherapy library. The content of the item library includes a taxonomy of patient-relevant endpoints
according to: organ system > immune reaction/condition > symptom profile > PRO questions [Figure 3].

Literature review
Our literature review yielded 25 articles documenting irAE incidence, management guidelines, toxicity
profiles, and associated symptomatology [4,9,11-15,40-57] . From these, we identified 75 possible inflammatory
reactions/immune conditions across 11 organ systems, ranging from very common to rare. Organ
systems were categorized as: (1) cutaneous; (2) gastrointestinal; (3) hepatic; (4) lung; (5) endocrine; (6)
musculoskeletal; (7) renal; (8) nervous; (9) hematologic; (10) cardiovascular; and (11) ocular. Identified
inflammatory reactions/conditions and their symptom profiles were summarized, and all associated
symptoms measurable by patient report were retained for PRO item mapping or development [Table 2]. We
identified a total of 142 unique symptoms, several of which overlap immune conditions. Symptoms include:
gastrointestinal [abdominal bloating, abdominal fullness, abdominal pain, abdominal swelling/distention,
pain radiating to the back, blood in stool, diarrhea, frequent bowel movements, constipation, heartburn
(burning chest pain), regurgitation, nausea, vomiting, vomiting blood, blood in stool, rectal bleeding, and
mouth sores]; skin (rash, rash-itch, rash-blisters, rash-pain, rash-burning, skin depigmentation, skin itch,
skin dryness, skin cracking/peeling, skin blisters, skin pain, skin thickening, skin thinning, nail pitting,
nail ridging, touch sensitivity, sun sensitivity, hair loss, and face reddening); lung (shortness of breath,
shortness of breath lying down, cough, cough lying down, wheezing, chest pain, chest pressure, and
edema); neurologic (coordination, balance, memory, confusion, disorientation, eyelid droop, facial droop,