Abstract
Background/Aim: Transient pain enhancement or flare pain, is observed following the administration of immune checkpoint inhibitors (ICIs). However, the detailed mechanism of this phenomenon remains unclear. In this report, we present our experience of documenting the course of flare pain following ICI administration in six cases. Patients and Methods: Six patients with advanced solid tumors received ICI monotherapy between July 2017 and November 2019. Their pain increased within hours of ICI administration despite being stable before ICI administration. We evaluated the changes in the numerical rating scale (NRS) score over 72 h after ICI administration. Results: Four non-small cell lung cancer patients, one gastric cancer patient, and one renal cell cancer patient were included. Four patients experienced an increase in NRS, as evidenced by scores on two or more scales compared to the day before administration, whereas two patients showed an increase only on one scale. The NRS score decreased to almost the same level as that on the day before administration. Flare pain is observed in the same area as the primary site. Most of the pain was alleviated without the need for rescue analgesics, although one patient experienced a 4-point increase in the NRS scale. Conclusion: Flare pain may occur following ICI administration. Healthcare providers should be aware of these events and provide patients with suitable information and coping techniques.
In recent years, cancer treatment involves the use of cytotoxic and molecular targeted therapies, in addition to combined treatment with immune checkpoint inhibitors (ICIs). ICI treatment is also associated with immune-related adverse events (irAEs) as a side effect, which present with various symptoms, including pneumonia, thyroid dysfunction, colitis, liver dysfunction, rashes, and type I diabetes.
Side effects other than irAEs include infusion reactions, and rarely, pain after administration. However, information on the latter is limited. In a phase 3 study of nivolumab administration in patients with advanced gastric cancer, 21.2% of 493 treated patients reported increased pain (1).
A case report has documented a 320% increase in opioid dosage in patients with head and neck cancer treated with nivolumab due to worsening cancer pain after administration (2). However, the detailed profile of temporary pain increase (flare pain) after ICI administration remains unknown.
In this study, we report our experience of several cases of transient pain enhancement (flare pain) during ICI administration despite stable pain before ICI administration.
Patients and Methods
Subjects. We analyzed cases of inpatients treated with nivolumab or pembrolizumab monotherapy at Atsugi City Hospital from July 2017 to November 2019. Flare pain was defined as pain with an increase of at least one point on the numerical ratio scale (NRS) despite stable pain on the day before ICI administration.
The NRS was recorded by a nurse, and the site of pain was defined as the primary site or metastases. A retrospective chart of the changes in NRS scores of patients with flare-up pain was reviewed.
Survey method. Patient background including age, sex, cancer type, presence or absence of metastases, performance status (Eastern Cooperative Oncology Group, ECOG), NRS on the day of ICI administration and one day before and after (day 1: day before administration, day 2: day of administration, day 3: day after administration), number of ICI administrations, time of ICI administration, and use of analgesics (opioids, NSAIDs, and acetaminophen) were studied.
Ethics considerations. This study was conducted following the Ethical Policy for Ethical Research and the Ethical Policy for Epidemiological Research and was approved by the Ethics Committee of Atsugi City Hospital (R1-107: approval date 14/11/2019).
Results
Patient background. During the study period, 17 patients were treated with nivolumab or pembrolizumab at enrollment. Of them, six patients had pain flares. The primary diseases in these patients were non-small cell lung cancer (adenocarcinoma) in three of them, non-small cell lung cancer (squamous cell carcinoma) in one, gastric cancer in one, and renal cell carcinoma in one. The ICI administered was nivolumab in five patients and pembrolizumab in one patient. The PS was less than 1 in all patients (Table I).
Patient background.
Changes in NRS on the day before, the day of, and the day after ICI administration. The NRS score increased by more than one point from the day before treatment in two patients. The remaining four patients showed an increase of more than two points. In all patients, the NRS score on the day after ICI administration returned to the same level as that on the day before ICI administration (Table II). Changes in NRS before and after ICI administration in each patient. Case 1 (Figure 1A): The patient was pain-free until the day before the first cycle of nivolumab administration but developed anterior chest pain with NRS=2 after nivolumab administration in the morning. No rescue analgesia was administered, and the pain resolved by 18:00 hours. Case 2 (Figure 1B): Persistent anterior chest pain with NRS=1 until the day before the first cycle of pembrolizumab administration, which increased to NRS=2 after ICI administration and decreased to NRS=1 at 18:00 hours. Case 3 (Figure 1C): The day before the seventh cycle of nivolumab administration, the pain remained at NRS=0-1; however, 150 min after nivolumab administration, flare pain at NRS=4 developed in the anterior chest and left iliac regions. It decreased to NRS=1 after rescue analgesia (oxycodone hydrochloride hydrate); case 3 experienced similar symptoms after three, four, five, and eight cycles. Case 4 (Figure 1D): The day before the first cycle of nivolumab administration, the pain remained at NRS=0-1 but starting 60 min after nivolumab administration, a flare of pain with NRS=3 developed from the right shoulder to the pericardial area. No rescue analgesia was administered, and the pain decreased to NRS=1 after 4 h. Case 5 (Figure 1E): The day before the first cycle of nivolumab administration, the patient was pain-free but developed lower abdominal pain of NRS=1 immediately after nivolumab administration. No rescue analgesia was used, and the pain resolved after 1 h. Case 6 (Figure 1F): Persistent numbness in the left lower limb with NRS=1 from the day before the first cycle of nivolumab administration was observed. At 180 min after nivolumab administration, NRS=5 developed numbness in the left lower limb and back pain occurred with body movement. Rescue analgesia was not requested by the patient, and the pain decreased to NRS=1 by 18:00 hours.
Changes in scores on the pain scale on the day before, the day of, and 1 day after ICI administration.
Changes in numerical rating scale (NRS) before and after immune checkpoint inhibitor administration in each patient. A) Case 1, B) Case 2, C) Case 3, D) Case 4, E) Case 5, F) Case 6. ★Rescue analgesic administration; Mor: morning; Mid: midday; Eve: evening.
Discussion
During the study period, 17 patients received ICI monotherapy upon admission. Of these, six (35%) showed pain exacerbation. All patients generally were in good condition (PS1 or less), and pain was controlled with analgesics (opioids and acetaminophen in one patient, opioids and NSAIDs in three patients, and opioids, NSAIDs, and acetaminophen in one patient) the day before ICI administration. All patients receiving in-hospital chemotherapy showed all symptoms, including pain, which were objectively and routinely observed by multiple trained healthcare professionals. The reliability of flare pain assessment after ICI administration appeared to be high because of the retrospective review of patients with pain.
Because the six cases reported herein were of patients with advanced cancer with some type of cancer pain, they were all treated with opioids, acetaminophen, and NSAIDs, and their pain was controlled. However, in all cases, pain flare-ups occurred immediately after ICI administration. The number of ICI doses was one in all five cases but one patient who was symptomatic upon receiving the seventh dose experienced similar symptoms in the previous cycle. This suggests that the contingency of pain exacerbation was low and ICIs may have triggered some type of pain exacerbation.
Pain flare-ups at the first ICI administration may be related to the cytokine release syndrome due to immune system disturbances in the infusion response. The incidence of infusion reactions with nivolumab and pembrolizumab is approximately 3-5% (3, 4); these effects cannot be ruled out, as many of these six cases developed upon first ICI administration. In Case 1 and 2, the patients had associated symptoms such as headache, and in Case 5, abdominal distension was observed. The mechanisms responsible for these flares were unclear.
In vivo studies in mice suggest that programmed cell death 1 ligand 1 (PD-L1) and programmed cell death 1 (PD-1) modulate opioid receptor signaling and cause opioid-induced nociceptive pain in rodents and primates (5). Pain exacerbation has been observed by blocking PD-L1 or PD-1 in mouse models of malignant melanoma following the administration of anti-PD-1 antibody drugs (6). The effect of an increase in NRS of ≥4 after ICI administration, as in cases 3 and 6, may be related to these mechanisms. Other possibilities include ICI-induced arthralgia, which occurs in 13.6% of patients treated with ICIs and is associated with the likelihood of developing another irAE, such as adrenal insufficiency, or treatment response (improved OS) (7, 8). The possibility of ICI-induced arthralgia cannot be ruled out, as case 4 had arthralgia around the right shoulder and case 6 had lower back pain at a different site from that of the cancer. As the present study was a single-center case series of six cases, it is necessary to observe the actual situation and mechanism of ICI-induced pain flares in a larger number of cases.
Many patients with cancer experience pain (9-11). In patients with cancer who are already taking analgesics, the increase in pain caused by ICI administration may be masked. In contrast, patients not taking analgesics may experience greater pain amplification. Healthcare professionals may underestimate flare pain as a transient and incidental event and should be aware of the possibility of these unknown phenomena.
Conclusion
Patients treated with ICIs may experience a pain flare-up at the primary site or joints after administration. Healthcare professionals should inform patients in advance that their flare-up pain is transient and encourage the use of rescue medications if symptoms are severe.
Footnotes
Authors’ Contributions
Yasumasa Saito and Junya Sato developed the research idea and methodology and analyzed the data. Tokiwa Takeshima and Hiroki Kase assisted in data collection under the supervision of Yasumasa Saito. Yasumasa Saito provided a summary of the clinical analysis of the study data and assisted with manuscript preparation and editing. All Authors reviewed the final manuscript and agreed to submit it.
Conflicts of Interest
The Authors declare no conflicts of interest in relation to this study.
- Received November 16, 2023.
- Revision received December 19, 2023.
- Accepted December 20, 2023.
- Copyright © 2024 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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