Rapid protocol for irinotecan desensitization: a case report and literature review

Irinotecan—an antineoplastic drug that inhibits topoisomerase I—is widely used to treat gastrointestinal malignancies. IgE-mediated hypersensitivity reactions (HSRs) to irinotecan are rarely described to date and successfully treated by a rapid drug desensitization (RDD) protocol. Chemotherapy desensitization is reported as a safe and effective way to reintroduce a culprit drug that often represents the firstline drug therapy. RDD should always be considered, particularly when there are no other valid therapeutic approaches in terms of life expectancy and quality of life. The RDD induces a temporary tolerance to drug allergens by gradually reintroducing a small amount


Background
Irinotecan-an antineoplastic drug that inhibits topoisomerase I-is widely used to treat gastrointestinal malignancies. IgE-mediated hypersensitivity reactions (HSRs) to irinotecan are rarely described to date and successfully treated by a rapid drug desensitization (RDD) protocol. Chemotherapy desensitization is reported as a safe and effective way to reintroduce a culprit drug that often represents the firstline drug therapy. RDD should always be considered, particularly when there are no other valid therapeutic approaches in terms of life expectancy and quality of life. The RDD induces a temporary tolerance to drug allergens by gradually reintroducing a small amount of the antigen over a relatively short period of time until the total scheduled dose has been administrated.
We present the case of a patient affected by pancreas adenocarcinoma who developed an immediate HSR to irinotecan who unsuccessfully underwent a standard chemotherapy RDD protocol.

Case report
We report a case of a 46-year-old man affected by locally advanced pancreas adenocarcinoma. Neoadjuvant chemotherapy was administered with the FOLFIRINOX regimen (calcium levofolinate, fluorouracil, irinotecan and oxaliplatin) as first-line treatment. During the second administration of irinotecan, the patient presented dyspnea with labial and eyelid angioedema. Subsequently, the patient received a third dose of irinotecan with a slower infusion rate and with a previous corticosteroids dose reporting the same symptoms; he tolerated fluorouracil and oxaliplatin administration and continued with only FOLFOX regimen.
Considering that after 3 months the computed tomography (CT) showed local cancer progression and blood tests revealed an increase of tumor markers (Ca 19.9, CEA), the oncologist team decided to obtain a patient allergological evaluation in order to treat the patient with FOLFIRI regimen (5-fluorouracil, leucovorin, irinotecan).
Hence, we performed irinotecan prick test (20 mg/mL) and intradermal tests (2 mg/mL and 20 mg/mL) according to the indications of Alvarez-Cuesta et al. [1]. The 20 mg/mL intradermal test was positive (mean wheal of 6 mm with erythema). On the basis of this result, we diagnosed an irinotecan IgEmediated allergy.
Since the patient needed irinotecan to treat his disease, we proposed irinotecan desensitization using 286 Rapid protocol for irinotecan desensitization: a case report and literature review K mini-review a 12-step protocol adapted from Castells et al. [2] after premedication with corticosteroid and antihistamines (oral methylprednisolone 32 mg and cetirizine 10 mg from 48 h before and intravenous methylprednisolone 40 mg and chlorpheniramine 1 h before the infusion).
The irinotecan was diluted in 250 mL of saline solution and administered 100-fold diluted in solution A, 10-fold diluted in solution B and the concentration of solution C was calculated by subtracting the cumulative. At each step, the infusion rate was increased. Solutions were administered in an oncology service by well-trained nursing staff under allergist supervision. The patient tolerated the first cycle of desensitization therapy well, but during the second cycle he experienced severe systemic symptoms characterized by dyspnea and wheezing that lead to interruption of treatment.
Therefore, we decided to modify the desensitization protocol adding a further step with more diluted drug and increasing premedication with montelukast 10 mg. However, due to the severity of HSRs and considering the patient's clinical condition, the oncology team refused this new treatment approach.

Discussion
HSRs to a chemotherapeutic agent is defined as an unpredictable reaction whose signs and symptoms cannot be explained by toxicity of the drug and range from mild cutaneous manifestation to life-threatening anaphylaxis [3].
HSRs are increased in oncology patients, and their frequency has been reported to be 5-27% for platins, 10-30% for taxanes and 0.6-10% for specific monoclonal antibodies [4]. However, HSRs to irinotecan are less frequently observed and described to date. In the study of Alvarez Cuesta et al. [1], irinotecan was the suspected culprit drug in 11 of 186 patients (5.9%) referred to their department for desensitization over a 3-year period.
In case of HRS, the RDD protocol represents a standard of care to continue the necessary chemotherapy drugs when no alternative equally effective therapy is available. Indeed RDD induces a temporary toleration state through incremental administration of drug. Although the molecular basis of this desensitization remains incompletely understood, the most likely hypothesis is that RDD inhibits mast cell activation.
However, as in our case, the occurrence of breakthrough adverse reactions (BTRs) during RDD are reported in 10-40% of cases [2,5] and their severity is significantly associated with initial HSRs severity, history of drug allergy and previous exposure to chemotherapeutic agents. The BTRs, instead, do not seem to be related to type and dose of premedication.
In the literature, only three cases of irinotecan RDD are described without any reaction during the protocol unlike our case (Table 1; [6][7][8]).
These protocols differed only in terms of premedication; in the first case, it consisted only of corticosteroids and antihistamine therapy, while, in the second one, the pretreatment included oral 500 mg acetylsalicylic acid and oral 10 mg montelukast at 48 h and 24 h before and on the day of desensitization. This latter approach seems be associated with a reduction of BTR occurrence in comparison to methylprednisolone pretreatment, considering the role of prostaglandins D2 and leukotrienes in the mast cell activation [10].
In our case, the oncologist team stopped irinotecan therapy after the first BRT although it was not worse than the initial reaction without trying implementation of proposed premedication and it lead to an unsuccessfully RDD. For this reason, consensus between oncologist and allergist in the assessment and management of HSRs and RDD is always required in order to avoid discontinuation of chemotherapeutic drugs.
On the basis of our experience and variable irinotecan RDD outcome, more studies are needed to propose individualized premedications and desensitization protocols according to patient-specific risk stratification.

Conclusions
The irinotecan RDD protocol should be always carried out taking into consideration the "risk-benefit balance" in an appropriate setting and mainly applied to patients who have no other reasonable alternative, but have the obvious potential clinical benefit of further treatment with the culprit drug.
Thus, the fear of more severe reaction during irinotecan infusion should not lead the clinicians to interrupt the ongoing chemotherapic therapy. Indeed, RDD should be always evaluated as an individualized possible therapeutic route in patients with HSRs; con-