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Outpatient desensitization in selected patients with platinum hypersensitivity reactions
YGYNO-976682; No. of pages: 8; 4C: Gynecologic Oncology xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Review Article
Outpatient desensitization in selected patients with platinum hypersensitivity reactions David M. O'Malley a,⁎, Monica Hagan Vetter a, David E. Cohn a, Ambar Khan b, John L. Hays c a b c
Division of Gynecology Oncology, Department of Gynecology and Obstetrics, The Ohio State University College of Medicine, Columbus, OH 43220, USA Department of Pharmacy, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43220, USA Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA
H I G H L I G H T S • • • •
The primary risk factor for platinum hypersensitivity reactions is prior exposure. A new classification system for hypersensitivity reactions is proposed. A management algorithm for platinum hypersensitivity reactions is discussed. Outpatient desensitization of patients with prior reactions is feasible.
a r t i c l e
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Article history: Received 6 October 2016 Received in revised form 7 March 2017 Accepted 22 March 2017 Available online xxxx Keywords: Carboplatin Hypersensitivity reactions Desensitization
a b s t r a c t Platinum-based chemotherapies are a standard treatment for both initial and recurrent gynecologic cancers. Given this widespread use, it is important to be aware of the features of platinum hypersensitivity reactions and the subsequent treatment of these reactions. There is also increasing interest in the development of desensitization protocols to allow patients with a history of platinum hypersensitivity to receive further platinum based therapy. In this review, we describe the management of platinum hypersensitivity reactions and the desensitization protocols utilized at our institution. We also describe the clinical categorizations utilized to triage patients to appropriate desensitization protocols. © 2017 Elsevier Inc. All rights reserved.
Contents 1. 2.
Introduction . . . . . . . . . . . . . . . . . . . . . Epidemiology, mechanisms, and risk factors . . . . . . . 2.1. Incidence and risk factors for HSR . . . . . . . . 2.2. Mechanisms of platinum hypersensitivity reactions 2.3. Predicting carboplatin hypersensitivity reactions . 3. Classification of HSR . . . . . . . . . . . . . . . . . 4. Management of HSR . . . . . . . . . . . . . . . . . 4.1. Management of acute HSR . . . . . . . . . . . 4.2. Platinum desensitization protocols. . . . . . . . 4.3. Breakthrough hypersensitivity reactions . . . . . 5. Prevention of platinum hypersensitivity reactions . . . . 6. Summary . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . .
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⁎ Corresponding author. E-mail address: david.o'[email protected] (D.M. O'Malley).
http://dx.doi.org/10.1016/j.ygyno.2017.03.015 0090-8258/© 2017 Elsevier Inc. All rights reserved.
Please cite this article as: D.M. O'Malley, et al., Outpatient desensitization in selected patients with platinum hypersensitivity reactions, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.03.015
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1. Introduction Platinum-based chemotherapies are widely used in the treatment of gynecologic malignancies and are a standard treatment option for both initial therapy and recurrent disease. As a result of the widespread use of carboplatin and cisplatin, the management of platinum hypersensitivity reactions (HSR) is an important topic for practitioners in the treatment of gynecologic malignancies. The purpose of this article is to discuss the current classification system of HSR, to discuss clinical features used to triage patients with HSR to appropriate management algorithms, and to describe the management of platinum HSR and subsequent desensitizations with an emphasis on outpatient management strategies. 2. Epidemiology, mechanisms, and risk factors 2.1. Incidence and risk factors for HSR Carboplatin HSR affect an estimated 5% of the general oncologic population and occur at a rate of approximately 1% of all platinum administrations [1]. Improved survival in ovarian cancer patients has led to patients receiving multiple platinum-based regimens in the recurrent setting thus increasing total exposure to platinums. Additionally, HSR to platinum agents generally develop after multiple cycles of treatment. An incidence of HSR in up to 27% of patients receiving seven or more cycles of carboplatin has been reported [2,3]. This figure approaches the incidence of atopy in the general population which ranges from 19.4– 40% [4]. In patients receiving less than five cycles of platinum, the incidence of HSR is reportedly b1%. Platinum HSR are most commonly acute in nature. However, a rare but clinically challenging scenario is a late or “atypical” reaction that manifests after completion of treatment to 14 days following treatment [5]. These reactions are characterized by rash, facial flushing, and/or gastrointestinal symptoms. Given the potential for life-threatening HSR the identification of factors that increase HSR is important in order to institute preventative measures and be prepared to manage HSR in order to avoid poor outcomes. There have been a number of studies attempting to identify risk factors of HSR. Prior platinum exposure appears to be the primary risk factor for the development of HSR [2,6]. In one study of patients receiving carboplatin for all tumor types, patients who developed HSR had an average total lifetime dose of carboplatin of 3850 mg compared to 1792 mg in the patients who did not develop HSR [2]. A subset analysis of ovarian cancer patients confirmed patients that experienced HSR received an average of 5218 mg of carboplatin over their lifetime compared to non-reacting patients who received 3196 mg. Studies have also shown a correlation between the number of cycles of carboplatin administration and the development of HSR with a significant increase in the occurrence of HSR after seven cycles of treatment [7]. A number of other risks factors have been associated with an increased risk of HSR. In patients with recurrent disease, a longer interval from prior platinum exposure has been associated with an increased risk of HSR. In one study, 25.8% of patients with a platinum-free interval of b12 months had a HSR as opposed to 56.5% of patients with a platinum-free interval N 12 months [8]. A history of prior systemic allergic reactions appears to slightly increase the risk of development of HSR [2,9]. Li et al. reported an incidence of atopy of 44%in patients with HSR to platinum drugs [10], which is slightly higher than the incidence described in the general population. The schedule of administration of the platinum agent has also been associated with increased risk of HSR. In a pediatric population, weekly administration of carboplatin increased the rate of HSR from 2% to 30% [11]. However, the association of the frequency of administration of platinum and the incidence of HSR is less clear in the adult population [12]. A recent report identified deleterious BRCA mutations as an independent risk factor for platinum HSR [13]. In this retrospective study of 87 women receiving carboplatin and olaparib for treatment of
ovarian cancer, 93% of patients who developed a HSR had a deleterious BRCA1/2 mutation versus 50% of patients without HSR. Patients with a deleterious BRCA1/2 mutations also had onset of HSR at a lower cumulative exposure compared to patients without a BRCA mutation. The increase in HSR in BRCA mutation carriers was confirmed on multivariate analysis controlling for potential confounding variables with an odds ratio of 13.1 (2.6–65.4; p = 0.0017). Finally, it appears that, when combined with other cytotoxic chemotherapies, the agent given with the platinum impacts the risk of platinum HSR. In the randomized Gynecologic Cancer InterGroup (GCIG) CALYPSO study of carboplatin/paclitaxel (CP) versus carboplatin/ pegylated liposomal doxorubicin (CD) in platinum sensitive ovarian cancer, there was a significantly increased risk of HSR in patients treated with CP compared to CD (33% versus 16%, p b 0.001) [14]. Nearly half (46%) of the HSR in the CD arm occurred in cycle 1 compared to only 16% of HSR in the CP arm. The GCIG also found that patients N70 years old had significantly lower rates of HSR when treated with CP; however, there was no association with age on the rate of HSR in the CD arm. 2.2. Mechanisms of platinum hypersensitivity reactions Platinum hypersensitivity reactions were first noted in platinum refinery workers. These reactions, referred to as platinosis, consisted of both respiratory and dermatologic manifestations and ranged from mild to severe [15]. Once workers developed these symptoms, they were always symptomatic in platinum-containing environments; however, it was also noted that patients could be systematically desensitized. It has been postulated that HSR are type I, immunoglobin E (IgE) mediated hypersensitivity reactions [16]. In type I hypersensitivity reactions, IgE bound to mast cells and basophils become activated causing cross-linking of the IgE ultimately resulting in release of pharmacologically active mediators including histamine, leukotrienes and prostaglandins [8]. This is supported by the rapid onset of symptoms during or shortly following carboplatin infusion, positive skin tests in patients who then develop HSR, and the detection of platinum-specific IgE in patients. More recent research has suggested that there may be a component of Type IV hypersensitivity in platinum HSR. Type IV hypersensitivity reactions are delayed hypersensitivity reactions that are mediated by the release of cytokines from CD4 + helper T cells thereby causing activation of macrophages, neutrophils, or eosinophils [17]. Delayed hypersensitivity reactions tend to present with cutaneous manifestations ranging from mild (eczema or maculopapular eruptions) to life-threatening (bullous or exfoliative reactions including Stevens-Johnson syndrome or acute generalized exanthematous pustulosis). Research performed in metal refinery workers has shown an increase in platinum-salt specific T-cell subpopulations [18]. Furthermore, in vitro stimulation of antigen-presenting cells increased the frequency of specific subpopulation of T cells. This suggests a mixed mechanism involved in HSR which may explain the variation in the presentations of HSR. 2.3. Predicting carboplatin hypersensitivity reactions Skin testing for prediction of carboplatin HSR was first used in the 1990s [19,20]. Both epicutaneous and intradermal skin testing routes have been investigated and have been used before and after platinum HSR. As the incidence of HSR increases after the seventh cycle of carboplatin administration, most studies initiate skin testing after their sixth cycle [19–22]. The negative predictive value of carboplatin skin testing when performed prior to the development of a HSR ranges from 81 to 92% with a positive predictive value of 86% [19,21]. The rate of HSR in patients who undergo desensitization after having a positive skin test ranges from 14 to 43% [19]. When used after a HSR, the frequency of positive skin tests ranges from 66%–93% [19]. At our institution, we do not routinely utilize skin testing due to the wide range of
Please cite this article as: D.M. O'Malley, et al., Outpatient desensitization in selected patients with platinum hypersensitivity reactions, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.03.015
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predictive value though clearly skin testing is an option to help predict HSR. Wang et al. [23] advocated for a skin testing algorithm patients with prior HSR. In this algorithm, patients with a negative skin test undergo an eight-step desensitization protocol until they have undergone 2 successful desensitizations and subsequently have 3 negative skin tests. Nearly 20% of patients with HSR to carboplatin were able to discontinue desensitization infusions and return to the local outpatient setting for further treatment. Performing skin testing may help attempt to identify patients at risk for an initial HSR, but alternative strategies may be more practical for most experienced practitioners. 3. Classification of HSR There are multiple classification systems used to grade hypersensitivity reactions which results in challenges when attempting to describe the severity of a HSR. The Common Toxicity Criteria for Adverse Events (CTCAE) uses the terms “allergic reaction” and “anaphylaxis” to classify HSR, while the National Comprehensive Cancer Network (NCCN) Guidelines for Ovarian Cancer emphasize the treatment of HSR reactions rather than the classification of those reactions (Table 1) [24,25]. Both criteria include define reactions using subjective symptoms rather than using clearly defined clinical signs. In one small study of carboplatin HSR, the incidence of grade 1–2 reactions as defined by the CTCAE v3.0 was 66.7% while the incidence of grade 3–4 reactions was 33.3% [26]. Realizing the challenges of the existing grading systems of HSR, Brown proposed a clinical classification system for general HSR highlighting the importance of hypotension, hypoxia and central nervous system involvement in triaging patients with HSR to appropriate treatment [27]. In his study of 1149 systemic hypersensitivity reactions presenting to a single institution, a categorization system was created using logistic regression analyses of association between individual reaction features and hypotension and hypoxia. Mild reactions were defined by common objective skin features that were not correlated with hypoxia or hypotension while severe reactions defined by features with the highest correlation with either hypotension or hypoxemia. At our institution, we have attempted to overcome some of the limitations and vague definitions of the current classification systems by implementing our own clinical guidelines to allow patients to be stratified to appropriate desensitization protocols based on the clinical severity of previous reactions. (Table 2) [14]. These clinical guidelines have allowed us to categorize patients into moderate-low, moderate-standard, and high risk categories with minimal overlap between groups. These categories have been named to indicate that desensitization protocol to be utilized (e.g. ‘moderate – low’ for low risk and the shortened protocol).
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4. Management of HSR Preparation for possible HSR The NCCN recommends that both clinicians and patients be prepared for the possibility of a drug reaction [25]. Patients and their families should be counseled about the signs and symptoms of platinum HSR and instructed to report these to their treating team. Treatment should be completed in areas with appropriate medical equipment such as an ambulatory resuscitation cart and under the care of practitioners trained in advanced cardiac life support. Standing medication orders should be written for immediate treatment of severe drug reactions. Administration of antihistamines, H2-blockers, glucocorticoids, and epinephrine are often used in the acute management of HSR. By including standing medication orders in the order set for platinum-based regimens, there is no delay for administration of necessary medications in an acute HSR situation. Close monitoring by staff experienced to recognize platinum HSR in patients is mandatory with special emphasis given to those patients who have received six or more cycles or receiving re-treatment of platinum based regimen after a platinum-free interval. Furthermore, special attention should be given to younger patients particularly those with earlier stage cancer and/or multiple allergies. Close attention should also be given to patients with pre-load dependent cardiac lesions. These clinical scenarios have been found to be risk factors for more severe HSR [28,29]. In patients with a history of platinum HSR, desensitization procedures should be considered under the guidance of a specialist and healthcare team with experience in desensitization. 4.1. Management of acute HSR There are a number of protocols and articles describing the acute management of platinum HSR; however, no single standard desensitization protocol has been recommended [10,29–33]. Here we seek to describe a comprehensive management algorithm for platinum HSR used at our institution. In order to assure proper level of care for the management of platinum HSR we have divided the treatment algorithms into mild/moderate-low HSR (Fig. 1) and moderate-standard/severe HSR (Fig. 2). 4.2. Platinum desensitization protocols We have utilized three platinum desensitization protocols: shortened, standard, and prolonged (Fig. 3). The protocols vary by infusion rate, titration schedule (i.e. number of steps to get to the goal rate of infusion), the total time required to complete the infusion and the location/setting of the infusion desensitization [10]. A patient with a history of mild and moderate-low risk HSR are desensitized in an
Table 1 Current HSR classifications. CTC v4
Grade 1
Grade 2
Grade 3
Grade 4
Allergic reaction
Transient flushing or rash, drug fever b38 °C (b100.4 °F); intervention no indicated
Intervention or infusion interruption indicated; responds promptly to symptomatic treatment (e.g., antihistamines, NSAIDS, narcotics); prophylactic medications indicated for ≤24 h
Life-threatening consequences; urgent intervention indicated
Anaphylaxis
N/A
N/A
Prolonged (e.g., not rapidly responsive to symptomatic medication and/or brief interruption of infusion); recurrence of symptoms following initial improvement; hospitalization indicated for clinical sequelae (e.g., renal impairment, pulmonary infiltrates) Symptomatic bronchospasm, with or without urticaria; parenteral intervention indicated; allergy-related edema/angioedema; hypotension
NCCN Mild Hot flushing, rash, pruritus
N/A Severe Shortness of breath, changes in blood pressure requiring treatment, dyspnea, GI symptoms (nausea, vomiting)
Life-threatening consequences; urgent intervention indicated
Life-threatening (i.e. anaphylaxis) Acute onset, generalized hives, respiratory compromise, severe hypotension, GI symptoms (nausea, vomiting)
Please cite this article as: D.M. O'Malley, et al., Outpatient desensitization in selected patients with platinum hypersensitivity reactions, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.03.015
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Table 2 Clinical categorizations utilized to triage patients with HSR reactions to appropriate treatment. Brown Mild
N/A Moderate
Skin and subcutaneous tissues only included generalized erythema, urticarial, periorbital edema and angioedema Modified Mild OSU Pruritus, facial flushing, rash (localized, particularly palms and soles), drug fever b100.4 °F
Severe
Dyspnea, stridor, wheeze, nausea, vomiting, diaphoresis, chest or throat tightness or abdominal pain
Cyanosis or SpO2 b 92% at any stage, hypotension (SBP b 90 mm Hg in adult), confusion, collapse of incontinence
Moderate–low
Moderate–standard
Severe
Diffuse erythema or urticarial, nausea/vomiting, abdominal pain/bloating, sneezing, nasal congestion, dyspnea without hypoxia, tight throat without hypoxia, coughing/wheezing, drug fever 100.4 °F
Transient hypo/hypertension, transient tachycardia/bradycardia, transient chest pain, transient hypoxia, vision disturbances, ringing/pounding in ears, angioedema without anaphylaxis
Sustained hypo/hypertension, sustained tachy/bradycardia, sustained hypoxia despite use of oxygen, altered mental status, hallucination, disorientation, pre-syncope, syncope, anaphylaxis
Fig. 1. Algorithm for management of mild/moderate-low HSR during platinum infusion.
Please cite this article as: D.M. O'Malley, et al., Outpatient desensitization in selected patients with platinum hypersensitivity reactions, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.03.015
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Fig. 2. Algorithm for management of moderate-standard/severe HSR during platinum infusion.
outpatient setting utilizing a one-solution 4-step desensitization (shortened desensitization protocol), whereas patients with moderate-standard and severe HSR undergo a one-solution, 16-step desensitization (standard desensitization protocol). The 16-step desensitization can take place in either an outpatient infusion center (OP-IC) or outpatient acute care observation beds (OP-AC) [22]. Patients who display symptoms of further acute HSR during a 16-step desensitization or are unable to complete either above protocol due to further acute HSR are treated with a prolonged 3 bag desensitization protocol in an OP-AC. The one-solution 16-step desensitization (standard desensitization) protocol has several advantages over currently available protocols. First, and perhaps the most important advantage, is the effective delivery of
carboplatin is guaranteed. Most published platinum desensitization protocols start with a dilution of the medication within the range of 1:100–1:1000 dilutions, with subsequently increased concentrations of drug until a 1:1 dilution is reached [30–35]. As a result approximately 10% of the total dose is aliquoted into the first two bags of solution while 90% is in the last bag of 1:1 solution. Furthermore, these protocols divide the total dose among different bags with lower concentrations in the first two bags due to the concern that initiating a desensitization with the full amount of drug in a 1:1 dilution would result in the recurrence of the HSR and failure of the desensitization. However, since the concentrations of carboplatin in the first 2 bags is typically far below the minimum concentration threshold of 0.5 mg/ml that is recommended by
Please cite this article as: D.M. O'Malley, et al., Outpatient desensitization in selected patients with platinum hypersensitivity reactions, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.03.015
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Fig. 3. Desensitization protocols utilized at The Ohio State University.
the drug manufacturer, the stability of the drug and efficacy of the drug in solution cannot be guaranteed. The new one-solution desensitization approach avoids potential problems with multiple dilutions, utilization of unapproved minimum concentrations, and the necessity for multiple bags of carboplatin to complete the required dose. Second, the standard desensitization approach minimizes potential errors associated with calculation for multiple dilutions, multiple dose preparations and administration, which theoretically enhances patient safety. The use of the above described protocols has been widely accepted by patients and practitioners for its safety, convenience and resource utilization throughout our institution. Advantages of performing
desensitization in an outpatient setting include allowing more patients with a history HSR to be treated in a timely fashion. Patients can continue treatment under the direct supervision of their primary gynecologic oncologists or medical oncologist in the outpatient setting allowing for close supervision by the team that has a previously established relationship. Our initial experience with the four-step desensitization in patients with low and moderate low risk HSR has been previously reported [11]. In this series, 94 of 95 (98.9%) desensitization infusions were completed in 18 gynecologic oncology patients in the outpatient setting. This one-solution, 4-step desensitization protocol is highly effective
Please cite this article as: D.M. O'Malley, et al., Outpatient desensitization in selected patients with platinum hypersensitivity reactions, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.03.015
D.M. O'Malley et al. / Gynecologic Oncology xxx (2017) xxx–xxx
and requires less time, fewer steps and with less solutions than previously reported protocols. More importantly, this new outpatient protocol did not seem to compromise patient safety. Approximately 68% of desensitization infusions were completed without subsequent HSR. Mild and moderate breakthrough reactions occurred in 18 (19%) and 11 (12%) desensitization infusions, respectively. However, these infusions were able to be successfully completed with modification of the infusion. Only 1.1% of desensitization infusions were unable to be completed due to breakthrough reactions but acute hospitalization was not required. 4.3. Breakthrough hypersensitivity reactions Management of breakthrough HSR that occur during desensitization infusions is similar to management of initial HSR. If a breakthrough reaction occurs, the infusion is immediately suspended and intravenous diphenhydramine and/or hydrocortisone is administered. Intravenous famotidine is given to patients who experienced nausea or vomiting while albuterol can be administered for respiratory symptoms. Once the symptoms resolve and the patient is deemed medically appropriate to reinstitute therapy, the infusion can be resumed at the 50% of the rate at which the HSR occurred for 15 min. The rate will then be increased according to the desensitization protocol on which the breakthrough reaction was experienced. If a moderate breakthrough reaction occurred or a mild breakthrough reaction reoccurred N2 times during the same desensitization, we recommend further discussion with the treating physician or expert in HSR to decide whether to continue or discontinue desensitization. This discussion should include the risk and benefits of further attempts at desensitization in the picture of the severity and persistence of the symptoms. In the case of severe breakthrough HSR, epinephrine can be administered and repeated as necessary and the desensitization should be aborted. The patient should then be observed in the acute care hospital for further management. 5. Prevention of platinum hypersensitivity reactions Given the potential for significant morbidity and mortality associated with platinum HSR, there has been significant interest in prevention of platinum HSR. These options include alternative platinum agents or prophylaxis. Some groups have focused their attempt to minimize HSR in the prophylactic utilization of pre-medications or desensitization protocols. O'Cearbhaill et al. reported their experience in patients being retreated with second line or greater platinum-based therapy regimens that utilized an extended carboplatin infusion [36]. Patients without a history of platinum HSR received dexamethasone the night before and diphenhydramine and ranitidine immediately prior to the carboplatin. Patients receiving the extended infusion schedule received 1% of the carboplatin infusion in the first hour, 9% in the second hour and 90% in the third hour. There was a significant reduction of HSRs in patients who received the extended infusion over those receiving the standard infusion (3.4% versus 21%). Given this data, the extended infusion schedule is certainly an option for patients who are being retreated with platinum. Disadvantages of this extended schedule include the additional time which may not be a practical utilization of resources (especially since 80% of patients who would not have a HSR regardless of infusion schedule). Additionally, some or all of the benefit seen with the extended infusion may have been from the expanded pre-medications given prior to the platinum infusions as other studies have shown up to a 50% reduction of HSR with pretreatment with diphenhydramine, famotidine, and dexamethasone [37–40]. At our institution we utilize a standard pre-medication regimen for patients with a prior HSR which includes dexamethasone, diphenhydramine and famotidine. Another option to minimize platinum HSR may be substitution of a new platinum agent. In one study of oxaliplatin plus cyclophosphamide versus cisplatin plus cyclophosphamide in chemo-naive advanced ovarian cancer patients, less toxicity was found in the oxaliplatin arm with
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no statistically significant difference in progression-free and overall survival [41]. However, the success of substituting another platinum drug to avoid HSR has been variable and the true incidence of cross-reactivity remains unknown [6]. One of the largest studies to date reported 24 patients with carboplatin HSR who were all subsequently treated with cisplatin. Only one patient (4%) had a cisplatin HSR on the first cycle. A total of 25% of patients subsequently developed HSR to cisplatin, with a mean time to HSR of 3.4 cycles of cisplatin. It is important to note that no life-threatening reactions occurred within this series [42]. However, in another case series of seven patients with recurrent ovarian cancer and a history of carboplatin HSR who were treated with cisplatin, there was one fatal hypersensitivity reaction and a second moderate/severe reaction [43]. In another study, 46 patients with recurrent gynecologic malignancies and history of carboplatin HSR were treated with either cisplatin or oxaliplatin [44]. Two of 27 patients treated with oxaliplatin developed non-threatening hypersensitivity reactions and none of the 19 patients treated with cisplatin had a HSR. In a smaller report, nine of ten patients who failed carboplatin or cisplatin desensitization were subsequently treated with oxaliplatin and tolerated the therapy [45]. Historically oxaliplatin has been uncommonly used in gynecologic cancers as compared to carboplatin and cisplatin and further experience and research is needed. There are times in clinical practice where consideration is given to treat a patient with a history of HSR with a new platinum agent. For example, one may consider initiating treatment in a platinum sensitive ovarian cancer patient with a cisplatin containing regimen in a patient who has history of carboplatin HSR. Our practice has typically been to perform a shortened desensitization when a different platinum agent is used especially if the prior reaction was severe. It is always important to first counsel the patient of the risk and benefits and the same precautions should be taken as previously discussed and treatment should occur only in a center experienced in platinum HSRs. 6. Summary Platinum HSR occurring during the treatment of gynecologic malignancies continues to make a large impact on the ability to treat recurrent disease. Identification of patients at the highest risk of platinum HSR can minimize the morbidity from platinum HSR. Women receiving multiple lines of platinum therapy, long intervals between platinum lines, BRCA germline positive, and younger age are at an increased risk of platinum HSR. Future research should continue to emphasize the prevention and early recognition of platinum HSR in an effort to improve safety and quality while maximizing efficiency and satisfaction. An outpatient desensitization protocol can be used in patients with platinum HSR in a safe and efficient fashion for most HSR. This should be done only in centers with experience in the treatment of HSR. Experienced medical professionals are essential to recognize the signs and symptoms of platinum HSR and actively manage the potentially life threatening acute reactions that can occur. Many of these signs and symptoms are subtle upon presentation and prompt recognition is essential to minimize potentially morbid sequelae. A discussion of the risk and benefits with the patient should occur before attempting desensitization and careful patient selection is the key to success of outpatient desensitization. Conflict of interest statement The authors declare that there are no conflicts of interest.
References [1] P.A. DeMoor, Y. Matusov, C. Kelly, S. Olan, L. Barnachea, L.A. Bazhenova, A retrospective review of the frequency and nature of acute hypersensitivity reactions at a medium-sized infusion center: comparison to reported values and inconsistencies, J. Cancer 2 (2011) 153–164.
Please cite this article as: D.M. O'Malley, et al., Outpatient desensitization in selected patients with platinum hypersensitivity reactions, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.03.015
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Please cite this article as: D.M. O'Malley, et al., Outpatient desensitization in selected patients with platinum hypersensitivity reactions, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.03.015
Contents lists available at ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Review Article
Outpatient desensitization in selected patients with platinum hypersensitivity reactions David M. O'Malley a,⁎, Monica Hagan Vetter a, David E. Cohn a, Ambar Khan b, John L. Hays c a b c
Division of Gynecology Oncology, Department of Gynecology and Obstetrics, The Ohio State University College of Medicine, Columbus, OH 43220, USA Department of Pharmacy, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43220, USA Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA
H I G H L I G H T S • • • •
The primary risk factor for platinum hypersensitivity reactions is prior exposure. A new classification system for hypersensitivity reactions is proposed. A management algorithm for platinum hypersensitivity reactions is discussed. Outpatient desensitization of patients with prior reactions is feasible.
a r t i c l e
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Article history: Received 6 October 2016 Received in revised form 7 March 2017 Accepted 22 March 2017 Available online xxxx Keywords: Carboplatin Hypersensitivity reactions Desensitization
a b s t r a c t Platinum-based chemotherapies are a standard treatment for both initial and recurrent gynecologic cancers. Given this widespread use, it is important to be aware of the features of platinum hypersensitivity reactions and the subsequent treatment of these reactions. There is also increasing interest in the development of desensitization protocols to allow patients with a history of platinum hypersensitivity to receive further platinum based therapy. In this review, we describe the management of platinum hypersensitivity reactions and the desensitization protocols utilized at our institution. We also describe the clinical categorizations utilized to triage patients to appropriate desensitization protocols. © 2017 Elsevier Inc. All rights reserved.
Contents 1. 2.
Introduction . . . . . . . . . . . . . . . . . . . . . Epidemiology, mechanisms, and risk factors . . . . . . . 2.1. Incidence and risk factors for HSR . . . . . . . . 2.2. Mechanisms of platinum hypersensitivity reactions 2.3. Predicting carboplatin hypersensitivity reactions . 3. Classification of HSR . . . . . . . . . . . . . . . . . 4. Management of HSR . . . . . . . . . . . . . . . . . 4.1. Management of acute HSR . . . . . . . . . . . 4.2. Platinum desensitization protocols. . . . . . . . 4.3. Breakthrough hypersensitivity reactions . . . . . 5. Prevention of platinum hypersensitivity reactions . . . . 6. Summary . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . .
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⁎ Corresponding author. E-mail address: david.o'[email protected] (D.M. O'Malley).
http://dx.doi.org/10.1016/j.ygyno.2017.03.015 0090-8258/© 2017 Elsevier Inc. All rights reserved.
Please cite this article as: D.M. O'Malley, et al., Outpatient desensitization in selected patients with platinum hypersensitivity reactions, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.03.015
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D.M. O'Malley et al. / Gynecologic Oncology xxx (2017) xxx–xxx
1. Introduction Platinum-based chemotherapies are widely used in the treatment of gynecologic malignancies and are a standard treatment option for both initial therapy and recurrent disease. As a result of the widespread use of carboplatin and cisplatin, the management of platinum hypersensitivity reactions (HSR) is an important topic for practitioners in the treatment of gynecologic malignancies. The purpose of this article is to discuss the current classification system of HSR, to discuss clinical features used to triage patients with HSR to appropriate management algorithms, and to describe the management of platinum HSR and subsequent desensitizations with an emphasis on outpatient management strategies. 2. Epidemiology, mechanisms, and risk factors 2.1. Incidence and risk factors for HSR Carboplatin HSR affect an estimated 5% of the general oncologic population and occur at a rate of approximately 1% of all platinum administrations [1]. Improved survival in ovarian cancer patients has led to patients receiving multiple platinum-based regimens in the recurrent setting thus increasing total exposure to platinums. Additionally, HSR to platinum agents generally develop after multiple cycles of treatment. An incidence of HSR in up to 27% of patients receiving seven or more cycles of carboplatin has been reported [2,3]. This figure approaches the incidence of atopy in the general population which ranges from 19.4– 40% [4]. In patients receiving less than five cycles of platinum, the incidence of HSR is reportedly b1%. Platinum HSR are most commonly acute in nature. However, a rare but clinically challenging scenario is a late or “atypical” reaction that manifests after completion of treatment to 14 days following treatment [5]. These reactions are characterized by rash, facial flushing, and/or gastrointestinal symptoms. Given the potential for life-threatening HSR the identification of factors that increase HSR is important in order to institute preventative measures and be prepared to manage HSR in order to avoid poor outcomes. There have been a number of studies attempting to identify risk factors of HSR. Prior platinum exposure appears to be the primary risk factor for the development of HSR [2,6]. In one study of patients receiving carboplatin for all tumor types, patients who developed HSR had an average total lifetime dose of carboplatin of 3850 mg compared to 1792 mg in the patients who did not develop HSR [2]. A subset analysis of ovarian cancer patients confirmed patients that experienced HSR received an average of 5218 mg of carboplatin over their lifetime compared to non-reacting patients who received 3196 mg. Studies have also shown a correlation between the number of cycles of carboplatin administration and the development of HSR with a significant increase in the occurrence of HSR after seven cycles of treatment [7]. A number of other risks factors have been associated with an increased risk of HSR. In patients with recurrent disease, a longer interval from prior platinum exposure has been associated with an increased risk of HSR. In one study, 25.8% of patients with a platinum-free interval of b12 months had a HSR as opposed to 56.5% of patients with a platinum-free interval N 12 months [8]. A history of prior systemic allergic reactions appears to slightly increase the risk of development of HSR [2,9]. Li et al. reported an incidence of atopy of 44%in patients with HSR to platinum drugs [10], which is slightly higher than the incidence described in the general population. The schedule of administration of the platinum agent has also been associated with increased risk of HSR. In a pediatric population, weekly administration of carboplatin increased the rate of HSR from 2% to 30% [11]. However, the association of the frequency of administration of platinum and the incidence of HSR is less clear in the adult population [12]. A recent report identified deleterious BRCA mutations as an independent risk factor for platinum HSR [13]. In this retrospective study of 87 women receiving carboplatin and olaparib for treatment of
ovarian cancer, 93% of patients who developed a HSR had a deleterious BRCA1/2 mutation versus 50% of patients without HSR. Patients with a deleterious BRCA1/2 mutations also had onset of HSR at a lower cumulative exposure compared to patients without a BRCA mutation. The increase in HSR in BRCA mutation carriers was confirmed on multivariate analysis controlling for potential confounding variables with an odds ratio of 13.1 (2.6–65.4; p = 0.0017). Finally, it appears that, when combined with other cytotoxic chemotherapies, the agent given with the platinum impacts the risk of platinum HSR. In the randomized Gynecologic Cancer InterGroup (GCIG) CALYPSO study of carboplatin/paclitaxel (CP) versus carboplatin/ pegylated liposomal doxorubicin (CD) in platinum sensitive ovarian cancer, there was a significantly increased risk of HSR in patients treated with CP compared to CD (33% versus 16%, p b 0.001) [14]. Nearly half (46%) of the HSR in the CD arm occurred in cycle 1 compared to only 16% of HSR in the CP arm. The GCIG also found that patients N70 years old had significantly lower rates of HSR when treated with CP; however, there was no association with age on the rate of HSR in the CD arm. 2.2. Mechanisms of platinum hypersensitivity reactions Platinum hypersensitivity reactions were first noted in platinum refinery workers. These reactions, referred to as platinosis, consisted of both respiratory and dermatologic manifestations and ranged from mild to severe [15]. Once workers developed these symptoms, they were always symptomatic in platinum-containing environments; however, it was also noted that patients could be systematically desensitized. It has been postulated that HSR are type I, immunoglobin E (IgE) mediated hypersensitivity reactions [16]. In type I hypersensitivity reactions, IgE bound to mast cells and basophils become activated causing cross-linking of the IgE ultimately resulting in release of pharmacologically active mediators including histamine, leukotrienes and prostaglandins [8]. This is supported by the rapid onset of symptoms during or shortly following carboplatin infusion, positive skin tests in patients who then develop HSR, and the detection of platinum-specific IgE in patients. More recent research has suggested that there may be a component of Type IV hypersensitivity in platinum HSR. Type IV hypersensitivity reactions are delayed hypersensitivity reactions that are mediated by the release of cytokines from CD4 + helper T cells thereby causing activation of macrophages, neutrophils, or eosinophils [17]. Delayed hypersensitivity reactions tend to present with cutaneous manifestations ranging from mild (eczema or maculopapular eruptions) to life-threatening (bullous or exfoliative reactions including Stevens-Johnson syndrome or acute generalized exanthematous pustulosis). Research performed in metal refinery workers has shown an increase in platinum-salt specific T-cell subpopulations [18]. Furthermore, in vitro stimulation of antigen-presenting cells increased the frequency of specific subpopulation of T cells. This suggests a mixed mechanism involved in HSR which may explain the variation in the presentations of HSR. 2.3. Predicting carboplatin hypersensitivity reactions Skin testing for prediction of carboplatin HSR was first used in the 1990s [19,20]. Both epicutaneous and intradermal skin testing routes have been investigated and have been used before and after platinum HSR. As the incidence of HSR increases after the seventh cycle of carboplatin administration, most studies initiate skin testing after their sixth cycle [19–22]. The negative predictive value of carboplatin skin testing when performed prior to the development of a HSR ranges from 81 to 92% with a positive predictive value of 86% [19,21]. The rate of HSR in patients who undergo desensitization after having a positive skin test ranges from 14 to 43% [19]. When used after a HSR, the frequency of positive skin tests ranges from 66%–93% [19]. At our institution, we do not routinely utilize skin testing due to the wide range of
Please cite this article as: D.M. O'Malley, et al., Outpatient desensitization in selected patients with platinum hypersensitivity reactions, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.03.015
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predictive value though clearly skin testing is an option to help predict HSR. Wang et al. [23] advocated for a skin testing algorithm patients with prior HSR. In this algorithm, patients with a negative skin test undergo an eight-step desensitization protocol until they have undergone 2 successful desensitizations and subsequently have 3 negative skin tests. Nearly 20% of patients with HSR to carboplatin were able to discontinue desensitization infusions and return to the local outpatient setting for further treatment. Performing skin testing may help attempt to identify patients at risk for an initial HSR, but alternative strategies may be more practical for most experienced practitioners. 3. Classification of HSR There are multiple classification systems used to grade hypersensitivity reactions which results in challenges when attempting to describe the severity of a HSR. The Common Toxicity Criteria for Adverse Events (CTCAE) uses the terms “allergic reaction” and “anaphylaxis” to classify HSR, while the National Comprehensive Cancer Network (NCCN) Guidelines for Ovarian Cancer emphasize the treatment of HSR reactions rather than the classification of those reactions (Table 1) [24,25]. Both criteria include define reactions using subjective symptoms rather than using clearly defined clinical signs. In one small study of carboplatin HSR, the incidence of grade 1–2 reactions as defined by the CTCAE v3.0 was 66.7% while the incidence of grade 3–4 reactions was 33.3% [26]. Realizing the challenges of the existing grading systems of HSR, Brown proposed a clinical classification system for general HSR highlighting the importance of hypotension, hypoxia and central nervous system involvement in triaging patients with HSR to appropriate treatment [27]. In his study of 1149 systemic hypersensitivity reactions presenting to a single institution, a categorization system was created using logistic regression analyses of association between individual reaction features and hypotension and hypoxia. Mild reactions were defined by common objective skin features that were not correlated with hypoxia or hypotension while severe reactions defined by features with the highest correlation with either hypotension or hypoxemia. At our institution, we have attempted to overcome some of the limitations and vague definitions of the current classification systems by implementing our own clinical guidelines to allow patients to be stratified to appropriate desensitization protocols based on the clinical severity of previous reactions. (Table 2) [14]. These clinical guidelines have allowed us to categorize patients into moderate-low, moderate-standard, and high risk categories with minimal overlap between groups. These categories have been named to indicate that desensitization protocol to be utilized (e.g. ‘moderate – low’ for low risk and the shortened protocol).
3
4. Management of HSR Preparation for possible HSR The NCCN recommends that both clinicians and patients be prepared for the possibility of a drug reaction [25]. Patients and their families should be counseled about the signs and symptoms of platinum HSR and instructed to report these to their treating team. Treatment should be completed in areas with appropriate medical equipment such as an ambulatory resuscitation cart and under the care of practitioners trained in advanced cardiac life support. Standing medication orders should be written for immediate treatment of severe drug reactions. Administration of antihistamines, H2-blockers, glucocorticoids, and epinephrine are often used in the acute management of HSR. By including standing medication orders in the order set for platinum-based regimens, there is no delay for administration of necessary medications in an acute HSR situation. Close monitoring by staff experienced to recognize platinum HSR in patients is mandatory with special emphasis given to those patients who have received six or more cycles or receiving re-treatment of platinum based regimen after a platinum-free interval. Furthermore, special attention should be given to younger patients particularly those with earlier stage cancer and/or multiple allergies. Close attention should also be given to patients with pre-load dependent cardiac lesions. These clinical scenarios have been found to be risk factors for more severe HSR [28,29]. In patients with a history of platinum HSR, desensitization procedures should be considered under the guidance of a specialist and healthcare team with experience in desensitization. 4.1. Management of acute HSR There are a number of protocols and articles describing the acute management of platinum HSR; however, no single standard desensitization protocol has been recommended [10,29–33]. Here we seek to describe a comprehensive management algorithm for platinum HSR used at our institution. In order to assure proper level of care for the management of platinum HSR we have divided the treatment algorithms into mild/moderate-low HSR (Fig. 1) and moderate-standard/severe HSR (Fig. 2). 4.2. Platinum desensitization protocols We have utilized three platinum desensitization protocols: shortened, standard, and prolonged (Fig. 3). The protocols vary by infusion rate, titration schedule (i.e. number of steps to get to the goal rate of infusion), the total time required to complete the infusion and the location/setting of the infusion desensitization [10]. A patient with a history of mild and moderate-low risk HSR are desensitized in an
Table 1 Current HSR classifications. CTC v4
Grade 1
Grade 2
Grade 3
Grade 4
Allergic reaction
Transient flushing or rash, drug fever b38 °C (b100.4 °F); intervention no indicated
Intervention or infusion interruption indicated; responds promptly to symptomatic treatment (e.g., antihistamines, NSAIDS, narcotics); prophylactic medications indicated for ≤24 h
Life-threatening consequences; urgent intervention indicated
Anaphylaxis
N/A
N/A
Prolonged (e.g., not rapidly responsive to symptomatic medication and/or brief interruption of infusion); recurrence of symptoms following initial improvement; hospitalization indicated for clinical sequelae (e.g., renal impairment, pulmonary infiltrates) Symptomatic bronchospasm, with or without urticaria; parenteral intervention indicated; allergy-related edema/angioedema; hypotension
NCCN Mild Hot flushing, rash, pruritus
N/A Severe Shortness of breath, changes in blood pressure requiring treatment, dyspnea, GI symptoms (nausea, vomiting)
Life-threatening consequences; urgent intervention indicated
Life-threatening (i.e. anaphylaxis) Acute onset, generalized hives, respiratory compromise, severe hypotension, GI symptoms (nausea, vomiting)
Please cite this article as: D.M. O'Malley, et al., Outpatient desensitization in selected patients with platinum hypersensitivity reactions, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.03.015
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Table 2 Clinical categorizations utilized to triage patients with HSR reactions to appropriate treatment. Brown Mild
N/A Moderate
Skin and subcutaneous tissues only included generalized erythema, urticarial, periorbital edema and angioedema Modified Mild OSU Pruritus, facial flushing, rash (localized, particularly palms and soles), drug fever b100.4 °F
Severe
Dyspnea, stridor, wheeze, nausea, vomiting, diaphoresis, chest or throat tightness or abdominal pain
Cyanosis or SpO2 b 92% at any stage, hypotension (SBP b 90 mm Hg in adult), confusion, collapse of incontinence
Moderate–low
Moderate–standard
Severe
Diffuse erythema or urticarial, nausea/vomiting, abdominal pain/bloating, sneezing, nasal congestion, dyspnea without hypoxia, tight throat without hypoxia, coughing/wheezing, drug fever 100.4 °F
Transient hypo/hypertension, transient tachycardia/bradycardia, transient chest pain, transient hypoxia, vision disturbances, ringing/pounding in ears, angioedema without anaphylaxis
Sustained hypo/hypertension, sustained tachy/bradycardia, sustained hypoxia despite use of oxygen, altered mental status, hallucination, disorientation, pre-syncope, syncope, anaphylaxis
Fig. 1. Algorithm for management of mild/moderate-low HSR during platinum infusion.
Please cite this article as: D.M. O'Malley, et al., Outpatient desensitization in selected patients with platinum hypersensitivity reactions, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.03.015
D.M. O'Malley et al. / Gynecologic Oncology xxx (2017) xxx–xxx
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Fig. 2. Algorithm for management of moderate-standard/severe HSR during platinum infusion.
outpatient setting utilizing a one-solution 4-step desensitization (shortened desensitization protocol), whereas patients with moderate-standard and severe HSR undergo a one-solution, 16-step desensitization (standard desensitization protocol). The 16-step desensitization can take place in either an outpatient infusion center (OP-IC) or outpatient acute care observation beds (OP-AC) [22]. Patients who display symptoms of further acute HSR during a 16-step desensitization or are unable to complete either above protocol due to further acute HSR are treated with a prolonged 3 bag desensitization protocol in an OP-AC. The one-solution 16-step desensitization (standard desensitization) protocol has several advantages over currently available protocols. First, and perhaps the most important advantage, is the effective delivery of
carboplatin is guaranteed. Most published platinum desensitization protocols start with a dilution of the medication within the range of 1:100–1:1000 dilutions, with subsequently increased concentrations of drug until a 1:1 dilution is reached [30–35]. As a result approximately 10% of the total dose is aliquoted into the first two bags of solution while 90% is in the last bag of 1:1 solution. Furthermore, these protocols divide the total dose among different bags with lower concentrations in the first two bags due to the concern that initiating a desensitization with the full amount of drug in a 1:1 dilution would result in the recurrence of the HSR and failure of the desensitization. However, since the concentrations of carboplatin in the first 2 bags is typically far below the minimum concentration threshold of 0.5 mg/ml that is recommended by
Please cite this article as: D.M. O'Malley, et al., Outpatient desensitization in selected patients with platinum hypersensitivity reactions, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.03.015
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Fig. 3. Desensitization protocols utilized at The Ohio State University.
the drug manufacturer, the stability of the drug and efficacy of the drug in solution cannot be guaranteed. The new one-solution desensitization approach avoids potential problems with multiple dilutions, utilization of unapproved minimum concentrations, and the necessity for multiple bags of carboplatin to complete the required dose. Second, the standard desensitization approach minimizes potential errors associated with calculation for multiple dilutions, multiple dose preparations and administration, which theoretically enhances patient safety. The use of the above described protocols has been widely accepted by patients and practitioners for its safety, convenience and resource utilization throughout our institution. Advantages of performing
desensitization in an outpatient setting include allowing more patients with a history HSR to be treated in a timely fashion. Patients can continue treatment under the direct supervision of their primary gynecologic oncologists or medical oncologist in the outpatient setting allowing for close supervision by the team that has a previously established relationship. Our initial experience with the four-step desensitization in patients with low and moderate low risk HSR has been previously reported [11]. In this series, 94 of 95 (98.9%) desensitization infusions were completed in 18 gynecologic oncology patients in the outpatient setting. This one-solution, 4-step desensitization protocol is highly effective
Please cite this article as: D.M. O'Malley, et al., Outpatient desensitization in selected patients with platinum hypersensitivity reactions, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.03.015
D.M. O'Malley et al. / Gynecologic Oncology xxx (2017) xxx–xxx
and requires less time, fewer steps and with less solutions than previously reported protocols. More importantly, this new outpatient protocol did not seem to compromise patient safety. Approximately 68% of desensitization infusions were completed without subsequent HSR. Mild and moderate breakthrough reactions occurred in 18 (19%) and 11 (12%) desensitization infusions, respectively. However, these infusions were able to be successfully completed with modification of the infusion. Only 1.1% of desensitization infusions were unable to be completed due to breakthrough reactions but acute hospitalization was not required. 4.3. Breakthrough hypersensitivity reactions Management of breakthrough HSR that occur during desensitization infusions is similar to management of initial HSR. If a breakthrough reaction occurs, the infusion is immediately suspended and intravenous diphenhydramine and/or hydrocortisone is administered. Intravenous famotidine is given to patients who experienced nausea or vomiting while albuterol can be administered for respiratory symptoms. Once the symptoms resolve and the patient is deemed medically appropriate to reinstitute therapy, the infusion can be resumed at the 50% of the rate at which the HSR occurred for 15 min. The rate will then be increased according to the desensitization protocol on which the breakthrough reaction was experienced. If a moderate breakthrough reaction occurred or a mild breakthrough reaction reoccurred N2 times during the same desensitization, we recommend further discussion with the treating physician or expert in HSR to decide whether to continue or discontinue desensitization. This discussion should include the risk and benefits of further attempts at desensitization in the picture of the severity and persistence of the symptoms. In the case of severe breakthrough HSR, epinephrine can be administered and repeated as necessary and the desensitization should be aborted. The patient should then be observed in the acute care hospital for further management. 5. Prevention of platinum hypersensitivity reactions Given the potential for significant morbidity and mortality associated with platinum HSR, there has been significant interest in prevention of platinum HSR. These options include alternative platinum agents or prophylaxis. Some groups have focused their attempt to minimize HSR in the prophylactic utilization of pre-medications or desensitization protocols. O'Cearbhaill et al. reported their experience in patients being retreated with second line or greater platinum-based therapy regimens that utilized an extended carboplatin infusion [36]. Patients without a history of platinum HSR received dexamethasone the night before and diphenhydramine and ranitidine immediately prior to the carboplatin. Patients receiving the extended infusion schedule received 1% of the carboplatin infusion in the first hour, 9% in the second hour and 90% in the third hour. There was a significant reduction of HSRs in patients who received the extended infusion over those receiving the standard infusion (3.4% versus 21%). Given this data, the extended infusion schedule is certainly an option for patients who are being retreated with platinum. Disadvantages of this extended schedule include the additional time which may not be a practical utilization of resources (especially since 80% of patients who would not have a HSR regardless of infusion schedule). Additionally, some or all of the benefit seen with the extended infusion may have been from the expanded pre-medications given prior to the platinum infusions as other studies have shown up to a 50% reduction of HSR with pretreatment with diphenhydramine, famotidine, and dexamethasone [37–40]. At our institution we utilize a standard pre-medication regimen for patients with a prior HSR which includes dexamethasone, diphenhydramine and famotidine. Another option to minimize platinum HSR may be substitution of a new platinum agent. In one study of oxaliplatin plus cyclophosphamide versus cisplatin plus cyclophosphamide in chemo-naive advanced ovarian cancer patients, less toxicity was found in the oxaliplatin arm with
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no statistically significant difference in progression-free and overall survival [41]. However, the success of substituting another platinum drug to avoid HSR has been variable and the true incidence of cross-reactivity remains unknown [6]. One of the largest studies to date reported 24 patients with carboplatin HSR who were all subsequently treated with cisplatin. Only one patient (4%) had a cisplatin HSR on the first cycle. A total of 25% of patients subsequently developed HSR to cisplatin, with a mean time to HSR of 3.4 cycles of cisplatin. It is important to note that no life-threatening reactions occurred within this series [42]. However, in another case series of seven patients with recurrent ovarian cancer and a history of carboplatin HSR who were treated with cisplatin, there was one fatal hypersensitivity reaction and a second moderate/severe reaction [43]. In another study, 46 patients with recurrent gynecologic malignancies and history of carboplatin HSR were treated with either cisplatin or oxaliplatin [44]. Two of 27 patients treated with oxaliplatin developed non-threatening hypersensitivity reactions and none of the 19 patients treated with cisplatin had a HSR. In a smaller report, nine of ten patients who failed carboplatin or cisplatin desensitization were subsequently treated with oxaliplatin and tolerated the therapy [45]. Historically oxaliplatin has been uncommonly used in gynecologic cancers as compared to carboplatin and cisplatin and further experience and research is needed. There are times in clinical practice where consideration is given to treat a patient with a history of HSR with a new platinum agent. For example, one may consider initiating treatment in a platinum sensitive ovarian cancer patient with a cisplatin containing regimen in a patient who has history of carboplatin HSR. Our practice has typically been to perform a shortened desensitization when a different platinum agent is used especially if the prior reaction was severe. It is always important to first counsel the patient of the risk and benefits and the same precautions should be taken as previously discussed and treatment should occur only in a center experienced in platinum HSRs. 6. Summary Platinum HSR occurring during the treatment of gynecologic malignancies continues to make a large impact on the ability to treat recurrent disease. Identification of patients at the highest risk of platinum HSR can minimize the morbidity from platinum HSR. Women receiving multiple lines of platinum therapy, long intervals between platinum lines, BRCA germline positive, and younger age are at an increased risk of platinum HSR. Future research should continue to emphasize the prevention and early recognition of platinum HSR in an effort to improve safety and quality while maximizing efficiency and satisfaction. An outpatient desensitization protocol can be used in patients with platinum HSR in a safe and efficient fashion for most HSR. This should be done only in centers with experience in the treatment of HSR. Experienced medical professionals are essential to recognize the signs and symptoms of platinum HSR and actively manage the potentially life threatening acute reactions that can occur. Many of these signs and symptoms are subtle upon presentation and prompt recognition is essential to minimize potentially morbid sequelae. A discussion of the risk and benefits with the patient should occur before attempting desensitization and careful patient selection is the key to success of outpatient desensitization. Conflict of interest statement The authors declare that there are no conflicts of interest.
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Please cite this article as: D.M. O'Malley, et al., Outpatient desensitization in selected patients with platinum hypersensitivity reactions, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.03.015