Impact of Carboplatin-Free Interval on Hypersensitivity Risks in Solid Tumor Patients with Silent Sensitization

Junyeong Jang; Jeong-Min Lee; Su Jeong Song; Eunyoung Sa; Young-Chan Kim; Hye‑Ryun Kang

doi:10.4143/crt.2025.1087

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Original Article Impact of Carboplatin-Free Interval on Hypersensitivity Risks in Solid Tumor Patients with Silent Sensitization: Junyeong Jang¹, Jeong-Min Lee¹, Su Jeong Song¹, Eunyoung Sa¹, Young-Chan Kim^1,2, Hye‑Ryun Kang^1,2,3; DOI: https://doi.org/10.4143/crt.2025.1087
Published online: May 8, 2026

¹Drug Safety Center, Seoul National University Hospital, Seoul, Korea

²Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea

³Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul National University College of Medicine, Seoul, Korea

Correspondence: Hye-Ryun Kang, Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea
Tel: 82-2-2072-0820 E-mail: helenmed@snu.ac.kr

• Received: October 3, 2025 • Accepted: May 6, 2026

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Abstract

Purpose
Carboplatin hypersensitivity reactions (HSRs) often occur after silent sensitization in patients with solid tumors through repeated uneventful exposures. The carboplatin-free interval (CFI) has been implicated in HSR risk, but its independent impact on previously asymptomatic yet sensitized patients, as well as temporal risk patterns, remains unclear. We aimed to identify risk factors for HSRs following carboplatin re-administration in patients who had completed prior carboplatin treatment without HSRs, and to clarify the temporal association between CFI and HSR risk.
Materials and Methods
We retrospectively analyzed patients with solid tumors who received carboplatin after CFI ≥ 2 months at Seoul National University Hospital (2014-2016), excluding those with prior HSRs. Multivariable logistic regression identified factors associated with HSRs. HSR incidence and severity were assessed across CFI strata (< 12, 12 to < 24, 24 to < 36, and ≥ 36 months).
Results
Among 258 patients with previous uneventful exposure, 52 (20.2%) developed HSRs, including 15 severe cases (5.8%). Independent risk factors were female sex (odds ratio [OR], 6.105; p=0.015), history of drug allergy (OR, 2.991; p=0.005), and CFI ≥ 12 months (OR, 2.198; p=0.030). Overall HSR incidence peaked at 33.3% with CFIs of 24-36 months, whereas severe HSRs were rare within 12 months but became progressively more frequent with longer CFIs, reaching the highest proportion beyond 36 months.
Conclusion
Longer CFI independently increases the risk of carboplatin-induced HSRs. These findings support using CFI as a predictor for individualized risk assessment, particularly for patients re-administered after CFIs of 24 to < 36 months, who may warrant closer monitoring and preventive strategies.
Key words: Carboplatin, Hypersensitivity, Risk factors

Introduction

Carboplatin, a second-generation platinum-based chemotherapy agent, remains a cornerstone in the management of ovarian, lung, and other malignancies. However, repeated exposure can lead to hypersensitivity reactions (HSRs), which may occur abruptly upon re-administration despite prior uneventful treatment cycles—a phenomenon often referred to as “silent sensitization” [1-5]. In the context of platinum-based chemotherapy, silent sensitization describes a clinically defined state in which patients have been previously exposed to carboplatin without experiencing overt HSRs, yet may already have developed underlying immunologic sensitization that becomes clinically manifest upon subsequent re-exposure. These reactions, ranging from pruritus to anaphylaxis, may disrupt treatment continuity and compromise patient safety [6,7].

The risk of carboplatin HSRs increases with cumulative exposure. One study reported rates rising from 27% at the 7th cycle in the first-line therapy to 44% during third-line retreatment [1-3]. Consistent with allergy practice guidance, the risk increases after multiple administrations and during retreatment settings [8,9]. Such reactions impair quality of life and threaten therapeutic efficacy, underscoring the need to identify predictive risk factors and their timing to guide preventive strategies.

Reported risk factors include cumulative carboplatin doses > 3,500 mg, more than seven treatment cycles, prior platinum exposure, a history of drug or food allergies, and genetic factors such as BRCA1/2 mutations [8-12]. Among these, the carboplatin-free interval (CFI)—the period between the last carboplatin dose and re-administration—has emerged as a notable predictor. Paradoxically, rather than shorter intervals, longer CFIs have been linked to higher HSR risk. For instance, in ovarian cancer, HSR incidence increased when CFIs exceeded 12 or 13 months [13,14], and a recurrence cohort showed elevated risk with a median CFI over 23 months [15]. Reviews and cohort reports also highlight retreatment and interval effects as contexts of heightened risk and sensitization [4,5,9]. Yet, these studies often included patients with prior HSRs, complicating the interpretation of CFI as an independent risk factor, especially in asymptomatic but potentially sensitized patients.

To address this gap, we focused exclusively on patients with no prior carboplatin-induced HSRs, enabling evaluation of CFI as an independent variable. By examining the association between CFI length and both HSR incidence and severity, this study aims to clarify the timing of highest risk and provide practical evidence to guide monitoring and preventive strategies.

Materials and Methods

1. Study subjects

This retrospective cohort study was conducted at Seoul National University Hospital using electronic medical records. Eligible patients received carboplatin-based chemotherapy between January 2014 and December 2016 and had at least one documented CFI ≥ 2 months prior to re-administration. Follow-up was completed in September 2024. Exclusion criteria were (1) CFI < 2 months, (2) receipt of carboplatin at another institution, or (3) any documented HSR before the first CFI.

HSRs were defined as symptoms including pruritus, flushing or erythema, angioedema, throat tightness, dyspnea, chest or back pain, and hypotension (or hypertension) [16]. Causality between carboplatin and HSRs was assessed using the World Health Organization–Uppsala Monitoring Centre (WHO-UMC) criteria. Severity was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) ver. 5.0, and reactions of grade ≥ 3 were considered severe.

2. Outcomes

The primary outcome was to identify patient-specific and treatment-related factors associated with HSRs following carboplatin re-administration after CFI. Collected data included demographics (age, sex, body mass index), clinical parameters (estimated glomerular filtration rate, serum creatinine), and history of drug allergy. Cancer-related variables included cancer type, stage, and chemotherapy regimen. Additional HSR-related data included timing, severity, symptoms, interventions, and co-administered premedications (e.g., antihistamines, steroids).

The secondary outcome was HSR incidence according to CFI length, defined as the period between two carboplatin administrations, with the subsequent exposure at least 2 months after the preceding one. Incidence was calculated as the proportion of patients with HSRs among those meeting the inclusion criterion. We set the minimum CFI threshold at ≥ 2 months to distinguish true re-administration after completion of a prior treatment course from brief inter-cycle delays. Most carboplatin-based regimens are administered every 3 weeks (or occasionally every 4 weeks); therefore, a ≥ 2-month interval (approximately ≥ 8 weeks) exceeds typical cycle intervals and minimizes misclassification of short postponements due to transient toxicity, scheduling issues, or patient-related factors as a CFI.

3. Statistical analysis

Continuous variables were expressed as medians with ranges and compared using the Mann-Whitney U test. Categorical variables were expressed as counts with percentages and compared using Pearson’s chi-square test or Fisher’s exact test.

Multivariable logistic regression was performed to identify factors independently associated with carboplatin-induced HSRs, with HSR occurrence coded as a binary outcome (yes=1, no=0). Covariates included in the multivariable model were selected based on statistical significance in univariable analyses (p < 0.05) and/or clinical relevance as potential confounders reported in prior studies. The final model included sex, age, cancer type, cumulative carboplatin exposure (dose and number of cycles), prior exposure to other platinum agents, drug allergy, and CFI. Adjusted odds ratios (ORs) with 95% confidence intervals were reported.

All statistical analyses were performed using SPSS ver. 29.0 (IBM Corp.). A two-tailed p < 0.05 was considered statistically significant.

Results

1. Characteristics of the study subjects

A total of 258 patients with a CFI ≥ 2 months were included. Among these, 52 patients (20.2%) experienced HSRs following carboplatin re-administration (Fig. 1). The majority were female (67.4%), with a median age of 58 years (range, 0 to 94 years). Gynecologic cancers were the most common diagnosis (52.3%), followed by lung cancer (22.5%) and other malignancies (25.2%). The median CFI was 12.2 months (range, 2.0 to 111.4 months), with a median of 10 carboplatin cycles and a cumulative median dose of 4,582.9 mg. A drug allergy history was present in 18.2%, and 20.2% had prior exposure to other platinum-based agents, exclusively to cisplatin; no patients had been exposed to oxaliplatin (Table 1).

Among the 52 patients with HSRs, most reactions occurred within one hour of administration (59.6%). Moderate reactions (CTCAE grade 2) were the most frequent (57.7%), with predominantly cutaneous manifestations such as pruritus and urticaria (86.5%). Cardiovascular involvement occurred in 32.7% of cases (Table 2).

2. Risk factors for carboplatin-induced HSRs

On multivariable logistic regression, three variables were independently associated with HSRs: female sex (OR, 6.105; p=0.015), CFIs ≥ 12 months (OR, 2.198; p=0.030), and a history of drug allergy (OR, 2.991; p=0.005) (Table 3). Age, cancer type, cumulative carboplatin dose, and prior other platinum exposure were not associated with HSRs. When CFI and cumulative carboplatin dose were modeled as continuous variables, no statistically significant linear associations with HSR occurrence were observed (data not shown).

3. CFI and HSR patterns

The median CFI was significantly longer in patients with HSRs compared to those without (19.8 vs. 10.5 months, p=0.001) (Fig. 2). When CFIs were stratified into 12-month intervals, the incidence of any HSRs was highest in the 24 to < 36-month group (33.3%). Severe HSRs (CTCAE grade ≥ 3) increased with longer CFIs, reaching 14.3% in the ≥ 36-month group.

Logistic regression confirmed these associations. Compared with patients with CFI < 12 months, the odds of any HSR were significantly higher in the 12 to < 24-month group (OR, 3.084; p=0.004) and the 24 to < 36-month group (OR, 3.733; p=0.010). In the ≥ 36-month group, the incidence was 23.8% with an OR of 2.333, which did not reach statistical significance (p=0.062) (Table 4).

For severe HSRs, the incidence remained relatively low in CFIs < 36 months but rose substantially in the ≥ 36-month group (14.3%; OR, 5.125; p=0.015). Although the ORs for the 12 to < 24-month and 24 to < 36-month groups were elevated (1.488; p=0.610 and 2.795; p=0.251, respectively), these differences were not statistically significant. Overall, any HSRs occurred most frequently in the 24 to < 36-month group, whereas severe HSRs were more common with CFIs ≥ 36 months.

Discussion

This study uniquely focused on patients with potential silent sensitization, thereby eliminating the confounding effect of prior HSRs and enabling a clearer assessment of independent risk factors. We found that female sex, history of drug allergy, and longer CFI were independently associated with carboplatin-induced HSRs, whereas cumulative dose, treatment cycles, and prior platinum exposure did not remain significant, in contrast to previous reports [10,11,17,18]. These findings underscore the distinct predictive role of host susceptibility and treatment-free interval, particularly in previously asymptomatic but potentially sensitized patients.

The temporal pattern observed is noteworthy: overall HSR incidence peaked at 24 to < 36 months, while severe reactions rose substantially beyond 36 months. This contrasts with earlier studies, which primarily reported overall incidence of carboplatin-induced HSRs without stratifying risk by reaction severity or by discrete CFI categories [3,10,16]. By contrast, our study separately evaluated both overall and severe HSRs across predefined CFI strata, allowing characterization of distinct temporal risk patterns.

Consistent with this non-linear temporal pattern, modeling CFI as a continuous variable did not demonstrate a statistically significant linear association with HSR risk, supporting the use of categorical CFI stratification to capture clinically meaningful high-risk periods. Similarly, cumulative carboplatin dose did not show a significant linear association with HSR risk when modeled as a continuous variable. These findings suggest that threshold-dependent or non-linear effects, rather than monotonic dose-response relationships, may underlie carboplatin hypersensitivity. The pattern suggests that different immunological processes may drive overall versus severe HSR risk. One hypothesis is that prolonged drug-free intervals allow persistence and affinity maturation of carboplatin-specific IgE and of memory B cells, amplifying immune response upon re-exposure [19-21]. Sustained priming of mast cells and basophils may also maintain heightened reactivity over time [22,23]. The progressive increase in severe HSRs with longer CFIs may therefore reflect persistent immune activation and a progressively lowered clinical threshold for hypersensitivity.

HSRs to different chemotherapeutic agents exhibit distinct clinical and immunologic patterns. For example, HSRs to paclitaxel typically occur during the first or second exposure and are frequently attributed to non–IgE-mediated mechanisms, including direct mast cell activation or reactions to solvent vehicles such as Cremophor EL, despite routine steroid and antihistamine premedication [2,6-8,11]. In contrast, carboplatin-induced HSRs generally arise after multiple uneventful exposures, often in retreatment settings, and are more consistent with delayed immunologic sensitization, including IgE-mediated mechanisms [1,2,5,7]. These distinctions underscore that the temporal risk patterns and predictors identified in the present study are specific to carboplatin and should not be extrapolated to other chemotherapeutic agents with fundamentally different hypersensitivity profiles.

The association with female sex and drug allergy history further highlights host susceptibility. Female predominance is consistent with prior pharmacovigilance reports and may be related to estrogen-driven mast cell activation, higher Th2 responsiveness, or sex-based genetic differences in immune regulation [10,24]. Likewise, a history of drug allergy likely reflects an atopic predisposition, increasing the likelihood of cross-sensitization and vigorous immune responses upon carboplatin rechallenge [10]. Together, these host-related factors emphasize the need to consider patient background alongside treatment variables in risk prediction.

Clinically, our findings support the use of the CFI as a practical component of risk stratification prior to carboplatin rechallenge [5]. Based on the observed temporal patterns, CFIs may be pragmatically categorized into three risk tiers. Patients with CFIs < 12 months appear to have a relatively lower risk of HSRs and may be managed with standard monitoring during infusion. In contrast, patients re-administered carboplatin after CFIs ≥ 12 months—particularly those in the 24 to < 36-month range—represent a higher-risk group for HSRs and may benefit from enhanced clinical vigilance, such as closer observation during infusion and extended post-infusion monitoring [25]. For patients with CFIs ≥ 36 months, in whom severe reactions were more frequent, a high-risk approach may be warranted, including preparedness for rapid intervention, consideration of modified premedication strategies, or early referral for desensitization protocols when ongoing platinum therapy is clinically indicated [6,26,27]. Integrating CFI-based risk tiers with patient-specific factors, including female sex and a history of drug allergy, may enable more individualized and clinically actionable monitoring strategies without compromising the efficacy of platinum-based treatment in sensitive disease settings [5,9,17].

This study offers several strengths. To our knowledge, it is the first to focus on silent sensitization patients, excluding prior HSRs. By analyzing both incidence and severity trends across CFI strata, we provide novel evidence that overall HSRs peak at intermediate CFIs, while severe HSRs rise progressively with longer CFIs. These insights can support refinement of clinical guidelines and inform practical decision-making in cancer care.

Nonetheless, several limitations should be acknowledged. The retrospective, single-center design may restrict generalizability. The sample size, though larger than many prior cohorts, remains relatively modest. Sensitivity analyses using alternative minimum CFI thresholds were not feasible owing to limited subgroup event counts in this retrospective cohort. Analyses were conducted at the patient level rather than per regimen, potentially introducing variability for patients who received multiple regimens. The heterogeneity of chemotherapy combinations prohibited evaluation of coadministered agents [28]. Furthermore, mechanistic exploration was not possible, as allergy testing (e.g., skin testing, basophil activation assays, serum IgE) was not systematically performed [29]. These gaps may have led to underestimation of the true biological mechanisms underlying the observed associations.

In conclusion, this study demonstrates that longer CFIs independently increase the risk of carboplatin-induced HSRs in silent sensitization patients, with severe reactions rising markedly at CFIs ≥ 36 months. Alongside female sex and drug allergy history, CFI represents a practical tool for individualized risk stratification. Identifying high-risk patients and implementing tailored preventive strategies are critical to ensuring treatment continuity and safety. Future multicenter prospective studies incorporating immunologic biomarkers are warranted to validate these findings, elucidate underlying mechanisms, and refine personalized approaches to carboplatin hypersensitivity.

NOTES

Ethical Statement

This study was approved by the Institutional Review Board of Seoul National University Hospital (IRB number: 2409-071-1570). The requirement for informed consent was waived due to the retrospective nature of the study.

Author Contributions

Conceived and designed the analysis: Jang J, Lee JM, Song SJ, Sa E, Kim YC, Kang HR.

Collected the data: Jang J.

Contributed data or analysis tools: Jang J, Lee JM, Song SJ, Sa E.

Performed the analysis: Jang J.

Wrote the paper: Jang J, Song SJ, Sa E, Kang HR.

Conflicts of Interest

Conflict of interest relevant to this article was not reported.

Funding

This work was supported by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health and Welfare, Republic of Korea (No. HI21C1372).

Fig. 1.

Enrollment of study patients. A total of 1,872 patients treated with carboplatin between 2014 and 2016 were screened, and 258 with a carboplatin-free interval (CFI) ≥ 2 months and no prior hypersensitivity reactions were included in the final analysis. CARB, carboplatin; HSR, hypersensitivity reaction; SNUH, Seoul National University Hospital.

Fig. 2.

Comparison of carboplatin-free interval between patients with and without hypersensitivity reactions. Median carboplatin-free interval was significantly longer in the hypersensitivity reaction (HSR) group compared with the non-HSR group.

Table 1.

Baseline demographic, clinical, and treatment characteristics of the study population

Variable	Value (n=258)
Female sex	174 (67.4)
Age (yr)	58.0 (0-94)
BMI (kg/m²)	22.1 (1.9-33.5)
eGFR (mL/min)	88.8 (22.7-257.0)
Type of cancer
Gynecologic cancer	135 (52.3)
Lung cancer	58 (22.5)
Others^a)	65 (25.2)
Carboplatin-free interval (mo)	12.2 (2.0-111.4)
No. of carboplatin cycles	10.0 (3-49)
Cumulative carboplatin dose (mg)	4,582.9 (520.0-15,404.0)
Drug allergy	47 (18.2)
Prior other platinum use	52 (20.2)

Values are presented as number (%) or median (range). BMI, body mass index; eGFR, estimated glomerular filtration rate.

^a) Includes adenocarcinoma of unknown primary sites, atypical teratoid rhabdoid tumor, Wilms tumor, pineoblastoma, osteosarcoma, retinoblastoma, neuroblastoma, medulloblastoma, glioblastoma, lymphoma, rectal/renal/bladder/breast/esophageal/peritoneal/tongue/endocrine cancer.

Table 2.

Clinical characteristics of carboplatin-induced hypersensitivity reactions

Variable	No. (%) (n=52)
Onset time of HSR
Within 1 hour	31 (59.6)
Within 1 day	14 (26.9)
More than 1 day	7 (13.5)
Severity of HSR
Mild	7 (13.5)
Moderate	30 (57.7)
Severe	15 (28.8)
Symptoms
Cutaneous	45 (86.5)
Cardiovascular	17 (32.7)
Respiratory	9 (17.3)
Gastrointestinal	9 (17.3)
Neurologic	5 (9.6)
Premedication for combination chemotherapy
No	9 (17.3)
Dexamethasone	7 (13.5)
Dexamethasone+chlorpheniramine	36 (69.2)
Skin test
Not performed	43 (82.7)
Performed	9 (17.3)
Negative	5 (55.6)^a)
Positive	4 (44.4)^a)

HSR, hypersensitivity reaction.

^a) Percentages for skin test results are calculated among patients who underwent testing (n=9).

Table 3.

Risk factors for carboplatin-induced HSR in patients with prior asymptomatic exposure (n=258)

Variable	No. (%) or median (range)		Adjusted OR	95% CI	p-value
Variable	Non-HSR (n=206)	HSR (n=52)	Adjusted OR	95% CI	p-value
Female sex	126 (61.2)	48 (92.3)	6.105	1.430-26.070	0.015
Age (yr)	58.0 (0-82)	55.5 (4-94)	1.008	0.983-1.034	0.514
Type of cancer
Gynecologic cancer	94 (45.6)	41 (78.8)	Reference
Lung cancer	51 (24.8)	7 (13.5)	1.018	0.257-4.022	0.980
Others^a)	61 (29.6)	4 (7.7)	0.430	0.121-1.530	0.192
Carboplatin-free interval (mo)
< 12	112 (54.4)	15 (28.8)	Reference
≥ 12	94 (45.6)	37 (71.2)	2.198	1.081-4.470	0.030
No. of carboplatin cycles	10.0 (3-49)	11.5 (4-33)	0.993	0.921-1.070	0.853
Cumulative carboplatin dose (mg)
< 4,500	106 (51.5)	19 (36.5)	Reference
≥ 4,500	100 (48.5)	33 (63.5)	0.804	0.308-2.100	0.656
Drug allergy	29 (14.1)	18 (34.6)	2.991	1.394-6.416	0.005
Prior platinum use	45 (21.8)	7 (13.5)	1.086	0.401-2.944	0.871

CI, confidence interval; HSR, hypersensitivity reaction; OR, odds ratio.

Table 4.

Incidence and logistic regression analysis of carboplatin-induced hypersensitivity reactions according to CFI length

CFI (mo)	Any HSR (n=52)				Severe HSR (n=15)
CFI (mo)	Incidence (%)	OR	95% CI	p-value	Incidence (%)	OR	95% CI	p-value
< 12 (n=127)	11.8	Reference			3.1	Reference
12 to < 24 (n=65)	29.2	3.084	1.444-6.588	0.004	4.6	1.488	0.323-6.856	0.610
24 to < 36 (n=24)	33.3	3.733	1.366-10.202	0.010	8.3	2.795	0.482-16.199	0.251
≥ 36 (n=42)	23.8	2.333	0.957-5.690	0.062	14.3	5.125	1.371-19.157	0.015

Observation period, median (range): 43.6 (5.6-130.5) months. CFI, carboplatin-free interval; CI, confidence interval; HSR, hypersensitivity reaction; OR, odds ratio.

REFERENCES

1. Makrilia N, Syrigou E, Kaklamanos I, Manolopoulos L, Saif MW. Hypersensitivity reactions associated with platinum antineoplastic agents: a systematic review. Met Based Drugs. 2010;2010:207084.Article PubMed PMC PDF
2. Tsao LR, Young FD, Otani IM, Castells MC. Hypersensitivity reactions to platinum agents and taxanes. Clin Rev Allergy Immunol. 2022;62:432–48. Article PubMed PDF
3. Markman M, Kennedy A, Webster K, Elson P, Peterson G, Kulp B, et al. Clinical features of hypersensitivity reactions to carboplatin. J Clin Oncol. 1999;17:1141.Article PubMed
4. Banerji A, Lax T, Guyer A, Hurwitz S, Camargo CA Jr, Long AA. Management of hypersensitivity reactions to carboplatin and paclitaxel in an outpatient oncology infusion center: a 5-year review. J Allergy Clin Immunol Pract. 2014;2:428–33. Article PubMed
5. Hesterberg PE, Banerji A, Oren E, Penson RT, Krasner CN, Seiden MV, et al. Risk stratification for desensitization of patients with carboplatin hypersensitivity: clinical presentation and management. J Allergy Clin Immunol. 2009;123:1262–7. Article PubMed
6. Castells MC, Tennant NM, Sloane DE, Hsu FI, Barrett NA, Hong DI, et al. Hypersensitivity reactions to chemotherapy: outcomes and safety of rapid desensitization in 413 cases. J Allergy Clin Immunol. 2008;122:574–80. Article PubMed
7. Castells M, Sancho-Serra MD, Simarro M. Hypersensitivity to antineoplastic agents: mechanisms and treatment with rapid desensitization. Cancer Immunol Immunother. 2012;61:1575–84. Article PubMed PMC PDF
8. Broyles AD, Banerji A, Barmettler S, Biggs CM, Blumenthal K, Brennan PJ, et al. Practical guidance for the evaluation and management of drug hypersensitivity: specific drugs. J Allergy Clin Immunol Pract. 2020;8(9 Suppl):S16–116. PubMed
9. Jang HY, Choi B, Kim IW, Kang HR, Oh JM. Risk factors of hypersensitivity reactions to carboplatin: a systematic review and meta-analysis. J Allergy Clin Immunol Pract. 2025;13:610–8. Article PubMed
10. Navo M, Kunthur A, Badell ML, Coffer LW 2nd, Markman M, Brown J, et al. Evaluation of the incidence of carbop hypersensitivity reactions in cancer patients. Gynecol Oncol. 2006;103:608–13. PubMed
11. Pagani M, Bavbek S, Alvarez-Cuesta E, Berna Dursun A, Bonadonna P, Castells M, et al. Hypersensitivity reactions to chemotherapy: an EAACI Position Paper. Allergy. 2022;77:388–403. Article PubMed PDF
12. Rolfe M, Gegeckas C, Turner S, Orr JW Jr. Predictive factors for carboplatin hypersensitivity reactions in gynecologic cancers: effect of BRCA status. J Oncol Pharm Pract. 2021;27:1704–9. Article PubMed PDF
13. Schwartz JR, Bandera C, Bradley A, Brard L, Legare R, Granai CO, et al. Does the platinum-free interval predict the incidence or severity of hypersensitivity reactions to carboplatin? The experience from Women and Infants’ Hospital. Gynecol Oncol. 2007;105:81–3. Article PubMed
14. Sugimoto H, Iwamoto T, Murashima Y, Tabata T, Sagawa N, Okuda M. Risk factors contributing to the development of carboplatin-related delayed hypersensitivity reactions in Japanese patients with gynecologic cancers. Cancer Chemother Pharmacol. 2011;67:415–9. Article PubMed PDF
15. Gadducci A, Tana R, Teti G, Zanca G, Fanucchi A, Genazzani AR. Analysis of the pattern of hypersensitivity reactions in patients receiving carboplatin retreatment for recurrent ovarian cancer. Int J Gynecol Cancer. 2008;18:615–20. Article PubMed
16. Polyzos A, Tsavaris N, Kosmas C, Arnaouti T, Kalahanis N, Tsigris C, et al. Hypersensitivity reactions to carboplatin administration are common but not always severe: a 10-year experience. Oncology. 2001;61:129–33. Article PubMed PDF
17. Tai YH, Tai YJ, Hsu HC, Lee SP, Chen YY, Chiang YC, et al. Risk factors of hypersensitivity to carboplatin in patients with gynecologic malignancies. Front Pharmacol. 2017;8:800.Article PubMed PMC
18. Hwang WY, Lee M, Suh DH, Kim K, No JH, Kim YB, et al. Risk factors for and prognosis of carboplatin-related hypersensitivity in patients with epithelial ovarian cancer. Arch Gynecol Obstet. 2022;306:443–9. Article PubMed PDF
19. Looney TJ, Lee JY, Roskin KM, Hoh RA, King J, Glanville J, et al. Human B-cell isotype switching origins of IgE. J Allergy Clin Immunol. 2016;137:579–86. Article PubMed
20. Oettgen HC. Fifty years later: emerging functions of IgE antibodies in host defense, immune regulation, and allergic diseases. J Allergy Clin Immunol. 2016;137:1631–45. Article PubMed PMC
21. Satitsuksanoa P, Iwasaki S, Boersma J, Bel Imam M, Schneider SR, Chang I, et al. B cells: the many facets of B cells in allergic diseases. J Allergy Clin Immunol. 2023;152:567–81. Article PubMed
22. Iwamoto T, Hirai H, Yamaguchi N, Kobayashi N, Sugimoto H, Tabata T, et al. Carboplatin-induced severe hypersensitivity reaction: role of IgE-dependent basophil activation and FcepsilonRI. Cancer Sci. 2014;105:1472–9. PubMed PMC
23. Steiner M, Harrer A, Himly M. Basophil reactivity as biomarker in immediate drug hypersensitivity reactions-potential and limitations. Front Pharmacol. 2016;7:171.Article PubMed PMC
24. Hox V, Desai A, Bandara G, Gilfillan AM, Metcalfe DD, Olivera A. Estrogen increases the severity of anaphylaxis in female mice through enhanced endothelial nitric oxide synthase expression and nitric oxide production. J Allergy Clin Immunol. 2015;135:729–36. Article PubMed
25. Boulanger J, Boursiquot JN, Cournoyer G, Lemieux J, Masse MS, Almanric K, et al. Management of hypersensitivity to platinum- and taxane-based chemotherapy: CEPO review and clinical recommendations. Curr Oncol. 2014;21:e630Article PubMed PMC
26. Mach CM, Lapp EA, Weddle KJ, Hunter RJ, Burns KA, Parker C, et al. Adjunct histamine blockers as premedications to prevent carboplatin hypersensitivity reactions. Pharmacotherapy. 2016;36:482–7. Article PubMed PDF
27. Tsao LR, Otani IM. One-bag desensitization protocols in the management of chemotherapy hypersensitivity. J Allergy Clin Immunol Pract. 2021;9:4055–9. Article PubMed
28. Pornwattanakrilert W, Suprasert P. Comparison of hypersensitivity reactions to carboplatin retreatment in gynecologic cancer patients between one and two hour infusions: a randomized trial study. Asian Pac J Cancer Prev. 2017;18:425–30. PubMed PMC
29. Bogas G, Ariza A, Vazquez-Revuelta P, Labella M, Madrigal-Burgaleta R, Fernandez-Santamaria R, et al. Basophil activation test is a complementary tool in the diagnosis of immediate reactions to platinum salts and taxanes. Allergy. 2025;80:271–86. Article PubMed

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Impact of Carboplatin-Free Interval on Hypersensitivity Risks in Solid Tumor Patients with Silent Sensitization

DOI: https://doi.org/10.4143/crt.2025.1087

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Abstract
Introduction
Materials and Methods
Results
Discussion
NOTES
REFERENCES

Impact of Carboplatin-Free Interval on Hypersensitivity Risks in Solid Tumor Patients with Silent Sensitization

Fig. 1. Enrollment of study patients. A total of 1,872 patients treated with carboplatin between 2014 and 2016 were screened, and 258 with a carboplatin-free interval (CFI) ≥ 2 months and no prior hypersensitivity reactions were included in the final analysis. CARB, carboplatin; HSR, hypersensitivity reaction; SNUH, Seoul National University Hospital.

Fig. 2. Comparison of carboplatin-free interval between patients with and without hypersensitivity reactions. Median carboplatin-free interval was significantly longer in the hypersensitivity reaction (HSR) group compared with the non-HSR group.

Fig. 1.

Fig. 2.

Impact of Carboplatin-Free Interval on Hypersensitivity Risks in Solid Tumor Patients with Silent Sensitization

Variable	Value (n=258)
Female sex	174 (67.4)
Age (yr)	58.0 (0-94)
BMI (kg/m²)	22.1 (1.9-33.5)
eGFR (mL/min)	88.8 (22.7-257.0)
Type of cancer
Gynecologic cancer	135 (52.3)
Lung cancer	58 (22.5)
Others^a)	65 (25.2)
Carboplatin-free interval (mo)	12.2 (2.0-111.4)
No. of carboplatin cycles	10.0 (3-49)
Cumulative carboplatin dose (mg)	4,582.9 (520.0-15,404.0)
Drug allergy	47 (18.2)
Prior other platinum use	52 (20.2)

Variable	No. (%) (n=52)
Onset time of HSR
Within 1 hour	31 (59.6)
Within 1 day	14 (26.9)
More than 1 day	7 (13.5)
Severity of HSR
Mild	7 (13.5)
Moderate	30 (57.7)
Severe	15 (28.8)
Symptoms
Cutaneous	45 (86.5)
Cardiovascular	17 (32.7)
Respiratory	9 (17.3)
Gastrointestinal	9 (17.3)
Neurologic	5 (9.6)
Premedication for combination chemotherapy
No	9 (17.3)
Dexamethasone	7 (13.5)
Dexamethasone+chlorpheniramine	36 (69.2)
Skin test
Not performed	43 (82.7)
Performed	9 (17.3)
Negative	5 (55.6)^a)
Positive	4 (44.4)^a)

Variable	No. (%) or median (range)		Adjusted OR	95% CI	p-value
Variable	Non-HSR (n=206)	HSR (n=52)	Adjusted OR	95% CI	p-value
Female sex	126 (61.2)	48 (92.3)	6.105	1.430-26.070	0.015
Age (yr)	58.0 (0-82)	55.5 (4-94)	1.008	0.983-1.034	0.514
Type of cancer
Gynecologic cancer	94 (45.6)	41 (78.8)	Reference
Lung cancer	51 (24.8)	7 (13.5)	1.018	0.257-4.022	0.980
Others^a)	61 (29.6)	4 (7.7)	0.430	0.121-1.530	0.192
Carboplatin-free interval (mo)
< 12	112 (54.4)	15 (28.8)	Reference
≥ 12	94 (45.6)	37 (71.2)	2.198	1.081-4.470	0.030
No. of carboplatin cycles	10.0 (3-49)	11.5 (4-33)	0.993	0.921-1.070	0.853
Cumulative carboplatin dose (mg)
< 4,500	106 (51.5)	19 (36.5)	Reference
≥ 4,500	100 (48.5)	33 (63.5)	0.804	0.308-2.100	0.656
Drug allergy	29 (14.1)	18 (34.6)	2.991	1.394-6.416	0.005
Prior platinum use	45 (21.8)	7 (13.5)	1.086	0.401-2.944	0.871

CFI (mo)	Any HSR (n=52)				Severe HSR (n=15)
CFI (mo)	Incidence (%)	OR	95% CI	p-value	Incidence (%)	OR	95% CI	p-value
< 12 (n=127)	11.8	Reference			3.1	Reference
12 to < 24 (n=65)	29.2	3.084	1.444-6.588	0.004	4.6	1.488	0.323-6.856	0.610
24 to < 36 (n=24)	33.3	3.733	1.366-10.202	0.010	8.3	2.795	0.482-16.199	0.251
≥ 36 (n=42)	23.8	2.333	0.957-5.690	0.062	14.3	5.125	1.371-19.157	0.015

Table 1. Baseline demographic, clinical, and treatment characteristics of the study population

Values are presented as number (%) or median (range). BMI, body mass index; eGFR, estimated glomerular filtration rate.

Includes adenocarcinoma of unknown primary sites, atypical teratoid rhabdoid tumor, Wilms tumor, pineoblastoma, osteosarcoma, retinoblastoma, neuroblastoma, medulloblastoma, glioblastoma, lymphoma, rectal/renal/bladder/breast/esophageal/peritoneal/tongue/endocrine cancer.

Table 2. Clinical characteristics of carboplatin-induced hypersensitivity reactions

HSR, hypersensitivity reaction.

Percentages for skin test results are calculated among patients who underwent testing (n=9).

Table 3. Risk factors for carboplatin-induced HSR in patients with prior asymptomatic exposure (n=258)

CI, confidence interval; HSR, hypersensitivity reaction; OR, odds ratio.

Table 4. Incidence and logistic regression analysis of carboplatin-induced hypersensitivity reactions according to CFI length

Observation period, median (range): 43.6 (5.6-130.5) months. CFI, carboplatin-free interval; CI, confidence interval; HSR, hypersensitivity reaction; OR, odds ratio.