A Case of Possible Infusion-Related Reactions Caused by Palonosetron

An infusion-related reaction (IRR) is a condition characterised by an adverse reaction to the infusion of a pharmacological or biological substance. Cytotoxic drugs or monoclonal antibodies are the most common cause of IRR. The most common signs and symptoms of IRR are rash, dyspnoea and hypotension. Other symptoms include chills, fever, diarrhoea, nausea and vomiting [1‒3]. Most IRRs are mild to moderate and occur during or a few hours after the infusion [4, 5]. Severe IRR is rare but can be fatal if not treated appropriately. It is therefore important to identify the causative agent and prevent severe IRR. In cases of severe IRR, the causative agent should be avoided. Meanwhile, in cases of mild to moderate IRR, strategies include assessing patients’ risk factors for IRR, adjusting infusion rates and using appropriate premedication. Corticosteroids, antihistamines and antipyretics are commonly used as premedication.

The 5-hydroxytryptamine 3 (5-HT3) receptor antagonists are recommended for the prevention of chemotherapy-induced nausea and vomiting (CINV). Palonosetron is a second-generation 5-HT3 receptor antagonist with strong binding affinity to the receptor and an extended half-life of approximately 40 h. The Phase III study showed that palonosetron was non-inferior to granisetron, a first-generation 5-HT3 receptor antagonist, in preventing CINV in the acute phase and significantly better in the delayed phase. The most common adverse events with palonosetron were constipation, increased serum aminotransferases and headache. No patient experienced IRRs in the clinical trial [6]. Here, we report a case of a patient who experienced recurrent IRRs following intravenous palonosetron.

A 75-year-old man diagnosed with resectable pancreatic ductal adenocarcinoma (clinical T3N0M0, stage IIA, UICC TNM 8th edition). His medical history included diabetes mellitus and no hypertension. He received neoadjuvant chemotherapy with gemcitabine plus tegafur/gimeracil/oteracil (S-1) followed by distal pancreatectomy. The pathological stage was IIB (pathological T3N1M0, UICC TNM 8th edition). The patient received adjuvant gemcitabine plus S-1 at the patient’s request. In the gemcitabine plus S-1 regimen, dexamethasone 6.6 mg was used to prevent CINV, followed by gemcitabine infusion over 30 min every 3 weeks. S-1 was administered from day 1 to day 14. There were no adverse events with either neoadjuvant or adjuvant chemotherapy. Liver metastases and lymph node recurrence were observed during adjuvant chemotherapy (Fig. 1). Liposomal irinotecan (nal-IRI) plus 5-fluorouracil and levofolinate (5-FU/l-LV) was then administered as palliative therapy. In the first cycle, 6.6 mg dexamethasone and 0.75 mg palonosetron were administered over 15 min to prevent CINV prior to nal-IRI. During the infusion of nal-IRI (50 min after the start of nal-IRI, 65 min after the start of premedication), the patient developed a fever of 39.1°C, chills and shivering, and an elevated systolic blood pressure of 160 mm Hg. A cholinergic syndrome or IRR caused by nal-IRI was considered and anticholinergic drugs were administered. Nal-IRI was temporarily interrupted and resumed at half the infusion rate after 30 min when the chills, shivering and hypertension improved. No further adverse events were observed. Laboratory tests showed no changes in inflammatory conditions such as elevated white blood cell counts or elevated C-reactive protein. In the second cycle, 9.9 mg of dexamethasone, d-chlorpheniramine maleate as an antihistamine, acetaminophen as an antipyretic and palonosetron were administered, followed by nal-IRI at half the infusion rate to prevent IRRs. During the infusion of nal-IRI (150 min after the start of nal-IRI, 165 min after the start of premedication), the patient developed a fever of 37.4°C. No other symptoms were observed and no change in treatment was required. After the second cycle of nal-IRI plus 5-FU/l-LV, computed tomography (CT) scans showed progression of liver metastases (Fig. 2).

The subsequent treatment was gemcitabine plus albumin-bound paclitaxel (nab-PTX). In the first cycle, patients received premedication with dexamethasone 6.6 mg and palonosetron, nab-paclitaxel and gemcitabine in that order. After all drugs were administered (90 min after the start of premedication), a fever of 38.0°C, chills, shivering, and an increase in systolic blood pressure to 160 mm Hg were observed. Oral acetaminophen was given and the symptoms improved within a few hours. The IRR was considered at the time to be due to nab-PTX as gemcitabine was used in perioperative therapy and no adverse events were observed. Symptoms improved with oral acetaminophen. Dexamethasone was increased to 9.9 mg and an antihistamine was added at the next dose. During the infusion of gemcitabine (17 min after the start of gemcitabine, 62 min after the start of premedication), a fever of 38.0°C, chills and an increase in systolic blood pressure to 180 mm Hg had occurred. As before, the symptoms improved with oral acetaminophen. After two infusions of gemcitabine plus nab-PTX, the treatment was changed due to disease progression.

The next treatment was oxaliplatin plus 5-FU/l-LV regimen. Premedication with dexamethasone 6.6 mg and palonosetron was given, followed by oxaliplatin. During the infusion of oxaliplatin and l-LV (45 min after the start of oxaliplatin and l-LV, 60 min after the start of premedication), the patient experienced chills, shivering and an increase in systolic blood pressure to 160 mm Hg. The IRR was considered to be due to oxaliplatin at that time and treatment was discontinued. Symptoms improved after 5 min without medication. In the second cycle, premedication was intensified with 13.2 mg of dexamethasone and antihistamine. However, a fever of 38.5°C, chills, shivering, and an increase in systolic blood pressure to 150 mm Hg were observed during the oxaliplatin infusion (81 min after starting oxaliplatin and l-LV, 96 min after starting premedication). Oxaliplatin was temporarily interrupted and hydrocortisone 100 mg was administered. The oxaliplatin infusion was resumed at half the infusion rate when the chills, shivering and hypertension improved. As tumour progression was observed after two cycles, the oxaliplatin plus 5-FU/l-LV regimen was discontinued.

Finally, the nal-IRI plus 5-FU/l-LV regimen was restarted at the patient’s request. In the first cycle, dexamethasone 9.9 mg, palonosetron and antihistamine were administered first. Nal-IRI was then administered at half the intended infusion rate to prevent IRRs. During the infusion of nal-IRI (57 min after the start of nal-IRI, 72 min after the start of premedication), a fever of 38.0°C, chills and shivering, an increase in systolic blood pressure to 195 mm Hg were observed. Treatment was temporarily interrupted and hydrocortisone 100 mg was administered. Nal-IRI was restarted at half dose after symptoms improved. In the second cycle, dexamethasone 6.6 mg, antihistamine and palonosetron were administered as premedication, followed by hydrocortisone 100 mg. During the hydrocortisone infusion (65 min after starting premedication), the patient developed a fever of 38.5°C, chills and shivering, and an elevated systolic blood pressure of 200 mm Hg. The symptoms improved spontaneously after 30 min and nal-IRI plus 5-FU/l-LV therapy was continued. No subsequent adverse events were observed. The patient was subsequently placed on palliative care due to disease progression.

Figure 3 shows each regimen and when IRRs occurred. In this case, symptoms of IRR did not occur during the infusion of palonosetron and mostly occurred during the infusion of cytotoxic agents. In addition, the median time from palonosetron infusion to symptoms was 73 min. These factors made it difficult to identify palonosetron as the cause of the IRR, and palonosetron was administered several times. To prevent IRRs, the premedication dexamethasone was increased to 9.9 or 13.2 mg, antihistamines were added and the nal-IRI dosing rate was slowed. However, the development of IRRs could not be suppressed and the severity of IRRs remained unchanged. Finally, as the IRR developed prior to the nal-IRI infusion during the reintroduction of nal-IRI plus 5-FU/l-LV therapy, we judged that palonosetron, which had been administered in all previous regimens where IRRs had occurred, was the causative agent.

IRRs induced by palonosetron are very rare, with only 2 cases reported to date [7, 8]. In both cases, anaphylaxis occurred during or immediately after palonosetron infusion. One case presented with dizziness, weakness, shortness of breath and severe hypotension. The other case had difficulty breathing, generalised pruritus, dizziness and severe hypoxia. The present case differs from these cases in that the symptoms were mild and the onset of symptoms was delayed after the intravenous injection of palonosetron.

IRRs are thought to occur by one of two mechanisms, immune-mediated or non-immune-mediated [4, 5]. Non-mediated reactions include 3 types: pseudoallergic (anaphylactoid reactions that resemble IgE antibody-mediated reactions with direct mast cell degranulation such as cytokine release syndrome), idiosyncratic (unusual, unpredictable, unrelated to the pharmacological action of the drug), and intolerance [5]. Symptoms caused by both mechanisms overlap, making identification difficult, but the different timing of their symptoms may help identify them. Non-immune-mediated reactions usually occur during or soon after the first infusion, whereas immune-mediated reactions are usually observed with subsequent exposures [9]. In the present case, symptoms occurred after the first infusion, but it is difficult to conclude that this is a non-immune-mediated mechanism.

It is controversial whether the symptoms observed in this case are IRRs. High fever, chills and shivering are common in infectious diseases. The possibility of infection is doubtful in this case as laboratory tests showed no change in inflammatory status and no persistent fever. Hypotension is typically seen in IRR, but in this case the patient had hypertension. Most patients with acute severe hypertension have hypertension as a comorbidity. Non-adherence to antihypertensive medication is an important trigger. It is also often triggered by excessive sodium intake, some drugs (e.g., cocaine, amphetamines, sympathomimetics, non-steroidal anti-inflammatory drugs and high-dose glucocorticoids), mental status such as anxiety or panic, and acute stroke or heart failure [10]. The patient in this case had no comorbidity of hypertension and received high doses of dexamethasone during perioperative chemotherapy, but did not have hypertension. Van Der Woude et al. [11] reported hypertension immediately after infusion of ramucirumab, an anti-vascular endothelial growth factor (VEGF) receptor inhibitor. The authors suggested that hypertension is one of the symptoms of IRRs and may involve pathways other than VEGF. In a study comparing the efficacy of granisetron and palonosetron in patients with malignant lymphoma, palonosetron was more frequently associated with hypertension (6.3% vs. 2.4%, p = 0.077) [12]. However, the timing of onset of hypertension was not reported and there is concern that this may be influenced by chemotherapy. Hypertension is also a symptom of the serotonin syndrome. Serotonin levels of 10–50 times baseline are required for serotonin syndrome to occur. 5-HT3 receptor antagonists alone are unlikely to cause serotonin syndrome, and combination with serotonin agonists or monoamine oxidase inhibitors (MAOIs) appears to be essential [13]. The symptoms seen in this case were included in serotonin syndrome, but serotonin syndrome was different because the patient was not taking serotonin agonists or MAOIs. We speculate that the hypertension may be an idiosyncratic response to non-immunogenic IRRs.

If IRRs are mild, they may be prevented by adjusting the dosing rate or intensifying premedication. In this case, discontinuation of palonosetron should be considered because IRRs occurred despite increasing the dose of dexamethasone and using antihistamines. The use of neurokinin-1 (NK1) receptor antagonists instead of palonosetron to prevent CINV is an option. Other 5-HT3 receptor antagonists such as granisetron should be used with caution due to the risk of IRR.

There were some limitations in this case. First, palonosetron was given repeatedly, although it was the causative agent of the IRR. The rarity of palonosetron-induced IRRs and the delayed onset of IRRs made it difficult to establish that palonosetron was the cause of the IRRs. We considered anticancer drugs as the cause of the IRRs until the last administration and intensified premedication. The IRR eventually developed before the anticancer drug was administered, allowing the causative agent to be identified. As all the IRR symptoms were not severe, we considered it reasonable to intensify the premedication and continue the anticancer treatment. Second, there was weak evidence that all IRRs were caused by palonosetron. The causative agent of an IRR is often identified based on the circumstances in which the IRR occurred (e.g., the drug administered, the frequency of IRRs reported in the past, etc.). Re-dosing only the suspected drug is most helpful in identifying the causative agent, but is not recommended if the IRR was severe. Naranjo et al. [14] have proposed an algorithm to assess the relationship between drugs and adverse events, with a score of 10, classified as definite, probable, possible or doubtful. In this case, the score was 2, which is classified as possible. Moreover, there was no opportunity to re-administer palonosetron due to disease progression. The possibility that a drug administered at the time of or immediately prior to the IRR, such as nal-IRI, gemcitabine, nab-PTX or oxaliplatin, may have been the cause of the IRR cannot be ruled out. However, there is no doubt that palonosetron was the cause of the IRR that occurred before the administration of nal-IRI in the last dose.

The patient with pancreatic cancer was receiving repeated courses of palonosetron to prevent CINV and developed chills, shivering, fever and hypertension after palonosetron administration. Although IRRs to palonosetron are rare and hypertension rarely occurs as an IRR, these symptoms were considered IRRs. The delayed onset of symptoms made it difficult to identify the causative agent. As palonosetron is widely used as prophylaxis for CINV, it must be acknowledged that IRRs may occur. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary Figure 1 (for all online suppl. material, see https://doi.org/10.1159/000543992).

This study was conducted in accordance with the Declaration of Helsinki of the World Medical Association. Ethical approval in accordance with local and national guidelines was not required because the patient data were reviewed retrospectively. Written informed consent was obtained from his kin for publication of this case report and any accompanying images because the patient has died.

The authors have no conflicts of interest to declare.

No research support was obtained for this report.

T.K. wrote the manuscript. H.K., H.Y., T.Y., and H.N. provided critical feedback and reviewed the data. All the authors have read and approved the final version of this manuscript.

The research data supporting this study are not available in a specific repository. For data access, please contact the corresponding author directly. The data that support the findings of this study are not publicly available due to containing information that could compromise the privacy of research participants but are available from the coauthor T.K. upon reasonable request.