Abstract
This cohort study assesses self-reported quality of life among patients referred to oncodermatology clinics for pruritus associated with immunotherapy.
Immunotherapies are landmark disease-modifying agents in cancer but have the potential to cause adverse events that can lead to treatment interruptions, decreased quality of life (QOL), or morbidity.1 Immunotherapy agents include monoclonal antibodies that target downregulators or checkpoints of the immune response, including cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), programmed cell death 1 (PD1), and programmed death ligand 1 (PD-L1), activating the immune system against tumor cells. Pruritus occurs in 14% to 47% of patients treated with immune checkpoint inhibitors and can range in severity from mild and localized to debilitating and widespread in 1% to 3% of patients.2 Pruritus in various dermatologic conditions is associated with lower QOL,3 but to our knowledge the repercussions of immunotherapy-related pruritus among patients with cancer have not been reported.
Methods
Patients referred to the oncodermatology clinics at Memorial Sloan Kettering Cancer Center in New York City and the University of Naples Federico II in Naples, Italy, for pruritus attributed to immunotherapy between December 1, 2014, and November 30, 2017, were given the ItchyQoL pruritus assessment, visual analog scale, and body distribution diagram. This study was approved by Memorial Sloan Kettering Cancer Center’s Institutional Review Board, and written informed consent was obtained from all participants. ItchyQoL is validated to assess QOL regarding pruritus symptoms, functional status, and emotional well-being. Each ItchyQoL item is scored from 1 to 5, with higher scores indicating greater burden on QOL.4 ItchyQoL is reported as a single score consisting of the mean of the responses to all the items. In the visual analog scale, participants rate their degree of itch on a 100-mm horizontal visual analog scale; possible scores range from 0 to 100, with a score of 0 indicating no itch and 100, extreme itch. Relevant clinical and demographic data were abstracted from electronic medical records. Pruritus was graded by following the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.5 Questionnaire responses and patient data were analyzed using SPSS, version 24 (IBM Corp); a 2-sided P < .05 was considered statistically significant.
Results
Seventy-nine patients evaluated by a dermatologist for pruritus attributed to immunotherapy were included; data were unavailable on pruritus grade, number of therapy cycles, and body distribution diagram for 2 patients. The mean (SD) age of patients was 63 (13) years, and 51 (65%) were male (Table). The primary cancer diagnosis was genitourinary in 28 patients (35%), melanoma in 16 (20%), and gastrointestinal in 12 (15%). Twenty-five patients (32%) received a diagnosis of pruritus in normal-appearing skin, and 36 (46%) presented with pruritus and a maculopapular eruption. Forty-nine patients (64%) received a diagnosis of grade 2 or 3 pruritus.
Table. Clinical Characteristics and Quality of Life in Patients With Cancer With Immunotherapy-Related Pruritus.
| Characteristic | No. (%) | P Valuea | |
|---|---|---|---|
| Pruritus With Eruption (n = 54) | Pruritus Only (n = 25) | ||
| Sex | |||
| Male | 33 (61) | 18 (72) | .35 |
| Female | 21 (39) | 7 (28) | |
| Age, mean (SD), y | 62 (11) | 63 (16) | .92 |
| Primary cancer | |||
| Genitourinary | 20 (37) | 8 (32) | .35 |
| Melanoma | 13 (24) | 3 (12) | |
| Gastrointestinal | 7 (13) | 5 (20) | |
| Lung | 7 (13) | 2 (8) | |
| Otherb | 7 (13) | 7 (28) | |
| Attributed immunotherapy | |||
| Anti–PD-1 | 20 (37) | 11 (44) | .76 |
| Combination anti-CTLA-4 + anti–PD-1/PD-L1 | 19 (35) | 8 (32) | |
| Anti–PD-L1 | 13 (24) | 6 (24) | |
| Anti–CTLA-4 | 2 (4) | 0 (0) | |
| Type of eruption | |||
| Maculopapular | 36 (67) | NA | |
| Bullous | 4 (7) | ||
| Lichenoid | 4 (7) | ||
| Otherc | 10 (19) | ||
| Pruritus grade by CTCAE version 4.0 | (n = 52) | (n = 25) | |
| Grade 0 or 1 | 16 (31) | 12 (48) | .14 |
| Grade 2 or 3 | 36 (69) | 13 (52) | |
| No. of therapy cycles before presentation, mean (SD) | 9 (10) | 11 (12) | .40 |
| ItchyQoL, mean (SD)d | (n = 54) | (n = 25) | |
| Overall score | 2.33 (0.81) | 2.20 (0.77) | .48 |
| Symptom | 2.45 (0.69) | 2.48 (0.89) | .87 |
| Function | 2.39 (0.95) | 2.14 (0.81) | .26 |
| Emotion | 2.21 (0.97) | 2.05 (0.91) | .50 |
| Visual analog scale score, mean (SD)e | 65 (24) | 66 (24) | .95 |
Abbreviations: CTCAE, Common Terminology Criteria for Adverse Events5; CTLA-4, cytotoxic T-lymphocyte–associated protein 4; NA, not applicable; PD-1, programmed cell death 1; PD-L1, programmed death ligand 1; QOL, quality of life.
Comparisons were performed using the t test and Pearson χ2. P values are 2-sided and unpaired.
Other primary cancers included brain cancer, head and neck squamous cell carcinoma, Merkel cell carcinoma, breast cancer, lymphoma, and sarcoma.
Other eruption types included acneiform, eczematous, psoriasiform, and urticarial.
The ItchyQoL patient-reported outcome questionnaire consists of 22 questions pertaining to pruritus symptoms, functional status, and emotional well-being. Responses are ranked on a 5-point scale. Scoring consists of 3 subscale (symptom, function, and emotion) scores and an overall score. The subscale scores consist of the average of the responses to the items in a given subscale. The overall score consists of the average of the responses to all the items.
Participants are asked to rate their degree of itch on a 100-mm horizontal visual analog scale where the left end indicates no itch and the right end indicates extreme itch. Scores reflect distance in millimeters from the left end of the scale and range from 0-100.
The mean (SD) ItchyQoL score was 2.29 (0.79), with a higher mean (SD) score among female compared with male patients (2.53 [0.80] vs 2.16 [0.77]; P = .04). Patients scored highest on the symptom domain (mean [SD] score, 2.46 [0.75]), followed by function (2.31 [0.92]) and emotion (2.16 [0.95]; P < .001). The median patient-rated degree of itch was 72 (interquartile range, 47-82) of 100 on a visual analog scale. Forty-two of 77 patients presented within the first 6 cycles of therapy (range of cycles, 1-58). The most common sites of pruritus included the trunk, and the least affected sites included the plantar feet, anterior neck, and genitalia (Figure). There was no significant difference in demographic characteristics, number of therapy cycles before presentation, pruritus severity, or QOL between patients with pruritus alone and patients with a coexisting eruption.
Figure. Itch Map of Frequency of Patient-Reported Pruritus on a Body Distribution Diagram.
Most pruritic corresponds to a maximum frequency of 64% of patients. Least pruritic corresponds to a minimum frequency of 1% of patients. Frequencies are expressed as percentages of all patients who completed this assessment.
Discussion
Pruritus related to immunotherapy is a frequent adverse event that is associated with lower patient QOL. Because the patients described herein were referred to an oncodermatology clinic, they likely represent patients with severe pruritus or pruritus that did not respond to oncologists’ interventions. Accordingly, severe (CTCAE grade 3) pruritus was common, with a mean ItchyQoL score greater than that found in patients receiving hemodialysis who reported chronic itch (2.29 vs 2.00).6 Immunotherapy-related pruritus has been described to involve the scalp,2 but our survey suggests anatomical involvement of the torso and extremities, with relative sparing of the head, neck, and acral areas.
There was no significant difference in how pruritus affected QOL between patients with and without a skin eruption, suggesting that pruritus without an eruption deserves attention and treatment in order to maintain QOL.
Immunotherapy-related pruritus represents a substantial burden on QOL in patients with cancer who are referred to a dermatologist. It demands attention and treatment even in normal-appearing skin given its association with reduced QOL and its potential to limit consistent administration of immunotherapy. Additional research is warranted to develop rational, pruritus-specific therapies that do not interfere with the activity of immunotherapies.
References
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