First daily carboplatin desensitization protocol in a child: A case report

Hypersensitivity reactions during chemotherapy, including anaphylaxis, have been increasingly reported.1 Younger age is a known risk factor for carboplatin hypersensitivity;2 in fact, hypersensitivity reactions have been described in 42% of children receiving carboplatin for low-grade glioma.3 Rapid drug desensitization is cost-effective and safe for allergic patients with cancer to remain on first-line therapy.4 Nowadays, few carboplatin desensitization protocols have been described yet for children,5, 6 most of them based on protocols for adults,7 such as the desensitization protocol to carboplatin in children with low-grade glioma recently described by Cernadas et al. 2021.5 It consists of a 12-step protocol with 3 bags (250 mL each, with different concentrations of the drug, administered at increasing rates) and usual premedication with antihistamine and methylprednisolone (1 mg/kg) 1 h before the infusion, intravenous hydration, and ondansetron. If needed, intermediate steps, a fourth bag, or premedication reinforcement can be added. Chemotherapy protocols are typically administered in their full dosage on a monthly basis; however, new protocols are being implemented with the aim of improving survival rates in pediatric neuro-oncology patients. A combination of radiotherapy and daily chemotherapy, using carboplatin as a radiosensitizing agent, has emerged as standard practice for a group of embryonal tumors.8 To the best of our knowledge, no daily chemotherapy desensitization protocol has been described for this unique situation yet. Given that this was a clinical case in which the patient required urgent chemotherapy, the parents agreed to undergo desensitization, at the suggestion of the medical staff. The local Research Ethics Committee was subsequently requested to review the publication of this clinical case. The authors describe a case of a 4-year-old male patient diagnosed with a group 3 metastatic (M2) medulloblastoma. Following a sub-total resection (>1.5 cm2 tumor remaining), the patient underwent a period of bridging chemotherapy prior to radiation therapy, which consisted of weekly vincristine (1.5 mg/m2) and carboplatin (175 mg/m2). Following this, the patient was transferred to our proton therapy unit for the delivery of radiotherapy. In accordance with the ACNS0332 protocol of Children's Oncology Group, the patient received weekly vincristine (0.9 mg, 1.5 mg/m2) and daily (from Monday to Friday) carboplatin (21 mg, 35 mg/m2), with premedication of ondansetron (2 mg, 0.15 mg/kg) intravenously (IV), concurrently with proton therapy. The drugs were administered through an implanted central venous catheter, “port-a-cath,” as the prior reported erythema was related to a peripheral infusion. Immediately after finalizing the ninth dose of carboplatin infusion (21 mg), the subject developed pruritic erythema on the chest, which resolved without treatment within a few hours. At the 10th dose, again immediately after finalizing the full diary dose (21 mg of carboplatin), a new set of symptoms emerged, characterized by the appearance of hives on the chest and facial regions, accompanied by nausea. These symptoms were resolved following the administration of intravenous infusion of methylprednisolone (20 mg, at a dose of 1.4 mg/kg), dexchlorpheniramine (3.5 mg, at a dose of 0.25 mg/kg), and pantoprazole (20 mg). Due to the urgent need to continue daily therapy during 4 weeks more, the next day of treatment we conducted a 12 step-desensitization protocol with carboplatin and premedication with IV ondansetron, IV hydration and IV dexchlorpheniramine 4 mg (0.25 mg/kg) based on Castells's protocol7 or Cernadas's protocol.5 However, daily administration required avoiding the use of corticosteroids and adjusting total volume of each solution (50 mL in solution A: 0.004 mg/mL, 50 mL in solution B: 0.042 mg/mL and 100 mL in solution C: 0.210 mg/mL). 30 min after starting step 12 (80 mL/h of solution C: 21 mg/mL in 100 mL) he developed same previous reaction that resolved with IV metylprednisolone 20 mg (1.4 mg/kg) and dexchlorpheniramine 4 mg (0.25 mg/kg). 24 h later, as proton therapy continued and the patient needed carboplatin, we added an intermediate step of 60 mL/h of solution C (0.210 mg/mL) (see Figure 1) and modified premedication by adding oral famotidine 10 mg (0.6 mg/kg) and changing IV dexchlorpheniramine for oral cetirizine 4 mg (0.25 mg/kg) with longer half-life, showing then good tolerance. That first week, as there were no other reports of daily chemotherapy desensitization and priorizing the safety of the child, the third day of desensitization we performed a 11 step-protocol with 2 bags (see Figure 2) (50 mL in solution B: 0.042 mg/mL and 100 mL in solution C: 0.210 mg/mL) starting with 1 mL/h of solution B (0.042 mg/mL), increasing every 15 min to 2 mL/h – 5 mL/h – 10 mL/h – 20 mL/h – 40 mL/h of solution B and then changing to solution C (0.210 mg/mL) starting at 10 mL/h and increasing every 15 min to 20 mL/h – 40 mL/h – 60 mL/h – 80 mL/h. The fourth and fifth day we performed an 8 step-protocol with 1 bag (see Figure 2) (100 mL in solution C: 0.210 mg/mL)starting with 1 mL/h of solution C: 0.210 mg/mL, increasing every 15 min to 2 mL/h – 5 mL/h – 10 mL/h – 20 mL/h – 40 mL/h – 60 mL/h – 80 mL/h showing good tolerance. Then we repeated the same scheme with good tolerance until finishing the treatment: the first day of the week 13 step-protocol with 3 bags, the second day of the week one bag-8 steps, and the next 3 days one bag-6 steps (see Figures 1 and 2). Everyday he received the same premedication (cetirizine, famotidine, montelukast, ondansetron and IV hydration) 30 min before carboplatin showing good tolerance. The use of daily low-dose carboplatin plus concurrent radiotherapy is increasing, particularly in cases of embryonal brain tumors affecting children and adults.8 It is also used in other tumors, such as lung cancer.9 As new radiation modalities become more widespread, such as proton therapy, which reduces acute and chronic toxicities and allows for new strategies, we expect to see an increase in the use of this approach. This case represented a challenge for several teams (Pharmacy Department, Department of Pediatrics, Radiation Oncology Department, Proton Therapy Unit, and Allergy Department) as we found no previous reports of daily desensitization to chemotherapeutic agents. The patient experienced a reaction on Friday, but chemotherapy and radiotherapy needed to continue the following Monday, and then daily from Monday to Friday for 4 weeks, without further reactions. Given the urgency, we planned a 12-step, 3-bag desensitization protocol as described by Cernadas et al.,5 while adjusting premedication (avoiding corticosteroids and modifying the administered volume). However, the patient developed another reaction, prompting us to modify the premedication and add an intermediate step, which was well tolerated. Because the patient was spending approximately 12 h per day at the hospital, our goal was to reduce this time without compromising safety. Every member of the team collaborated to achieve this. The duration of acute tolerance after antibiotic desensitization has been reported to vary from 2 to 5 half-lives.10 However, no such studies exist for chemotherapeutic agents. Moreover, the half-life of carboplatin in children is scarce and it varies from 2 to 6 h.11 As carboplatin is not routinely monitored, our pharmacology team did not have a standardized technique available. For safety reasons, we agreed to perform the 13-step carboplatin desensitization every Monday, after 72 h without carboplatin exposure. From Tuesday to Friday, since each dose was administered within less than 24 h of the previous one, we attempted a shortened desensitization protocol, as described for other drugs.12 First, we implemented a modified 8-step carboplatin desensitization protocol.13 Subsequently, to further reduce hospital stay without compromising safety, we tested a 6-step protocol. Ultimately, we succeeded in reducing hospital time by adapting the 13-step protocol (4 hours) into an 8-step protocol (3 h), and finally into a 6-step protocol (2 h 30 min), all without compromising safety. The rationale behind modifying the desensitization protocol by shortening the administration intervals was that, by administering the drug on a daily basis, we could exploit the temporary refractory period that follows a severe allergic reaction—during which reactivity is reduced—to enhance tolerability during desensitization.13, 14 We did not feel confident administering carboplatin at the usual infusion rate of 200–250 mL/h due to the patient's general condition, the risk of reaction, the lack of previous reports of daily desensitization, and the risk of missing a chemotherapy dose. In light of these developments, we have modified the traditional desensitization protocol5, 7 to optimize the daily carboplatin desensitization protocol through the following adjustments: reducing the total daily infusion volume, avoiding daily corticosteroids, using oral cetirizine instead of IV dexchlorpheniramine to prolong the antihistamine effect, and gradually withdrawing steps on a daily basis. Further studies are needed to determine how long the desensitization effect to chemotherapeutic agents lasts, in order to optimize drug delivery in this patient profile. L. Argiz: Conceptualization; investigation; methodology; writing – original draft; writing – review and editing; project administration; supervision; validation. T. Toscano: Investigation; conceptualization; supervision; writing – review and editing; methodology; validation; project administration. J. Crespo: Conceptualization; investigation; writing – review and editing; writing – original draft; methodology; validation. E. Panizo: Methodology; writing – review and editing; conceptualization; investigation. N. De Amuriza: Methodology; validation; writing – review and editing. M. Diaz Villapalos: Methodology; conceptualization; writing – review and editing. J. J. Aristu-Mendioroz: Methodology; investigation; writing – review and editing. G. Gastaminza: Conceptualization; investigation; writing – review and editing; methodology. This work was supported by Redes de Investigación Con Objetivos de Resultados en Salud (RICORS) – Red de Enfermedades Inflamatorias (REI) RD24/00070030, Instituto de Salud Carlos III and Next Generation EU funds. Authors declare to have no conflicts of interest. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/pai.70220.