The prophylactic conversion to an extended infusion schedule and use of premedication to prevent hypersensitivity reactions in ovarian cancer patients during carboplatin retreatment

doi:10.1016/j.ygyno.2009.10.070

Gynecologic Oncology

Volume 116, Issue 3, March 2010, Pages 326-331

https://doi.org/10.1016/j.ygyno.2009.10.070 Get rights and content

Abstract

Objective

Repeated exposure to carboplatin can lead to hypersensitivity reactions during retreatment with carboplatin. This may prevent its further use in platinum-sensitive ovarian cancer patients. At our institution, an increasing proportion of patients are prophylactically converted to an extended schedule of infusion after 8 cycles of carboplatin. We sought to determine whether an incrementally increasing, extended 3-hour infusion of carboplatin with appropriate premedication was associated with a lower rate of hypersensitivity reactions compared to the standard 30-minute schedule in sequentially treated patients.

Methods

We performed a retrospective electronic medical record review of patients with recurrent ovarian cancer retreated with carboplatin at our institution from January 1998 to December 2008.

Results

Seven hundred and seventy-seven patients with relapsed ovarian, fallopian tube, or primary peritoneal cancer were retreated with carboplatin and met study inclusion criteria. Of these, 117 (17%) developed hypersensitivity reactions during second-line or greater carboplatin-based treatment for recurrent disease. Only 6 (3.4%) of the 174 patients who received the extended schedule developed hypersensitivity reactions (0% grade 4; 50% grade 3) compared to 111 (21%) of 533 patients in the standard schedule group (13% grade 4; 77% grade 3). The first hypersensitivity episode occurred after a median of 16 platinum (carboplatin and cisplatin) treatments in the extended group compared to 9 in the standard group. Using the Fisher exact test, there was an association with a reduced incidence of hypersensitivity reactions with the extended infusion schedule (P < 0.001).

Conclusion

Our data suggest appropriate premedication and prophylactic conversion to an extended infusion during carboplatin retreatment may reduce hypersensitivity reactions.

Introduction

Hypersensitivity reactions (HSRs) can occur in epithelial ovarian cancer patients during retreatment with carboplatin, preventing further use of carboplatin. The risk of HSRs rises with increased lifetime carboplatin exposure and with a longer platinum-free interval [1], [2], [3]. Patients with recurrent epithelial ovarian cancer are frequently retreated with carboplatin for platinum-sensitive recurrent disease. The risk of HSRs in this population was as high as 44% in one series [4].

The clinical symptoms of carboplatin HSR are heterogeneous. Treatment of acute reactions with antihistamines and corticosteroids is often required. There is, however, the possibility of severe cardiopulmonary compromise, and even death, despite aggressive resuscitative efforts [3]. For this reason, in recurrent epithelial ovarian cancer, where treatment is noncurative and several alternative non-platinum-based options exist, one must weigh the risks and benefits of further carboplatin treatment.

The recently published 2009 National Comprehensive Cancer Network (NCCN) ovarian cancer guidelines recommend that patients are counseled regarding the risk of HSRs associated with repeat use of platinum drugs [5]. They emphasize the importance of educating patients about the symptoms of HSRs. In addition, they recommend that carboplatin retreatment is administered in an appropriately equipped medical setting by staff familiar with the management of HSRs. In patients who experience severe, life-threatening carboplatin HSR, further exposure to platinum agents should be avoided. In the case of less severe HSR, a desensitization protocol is recommended for any subsequent rechallenge with carboplatin.

Using a desensitization protocol, patients with a history of carboplatin HSR are sometimes able to receive additional platinum treatment. We hypothesized that, by prophylactically changing patients to a prolonged infusion in advance of HSR occurrence, the risk of developing HSR over the course of retreatment might be lessened. This became usual practice by several treating physicians at our center. We report the incidence of carboplatin HSRs among a large, retrospective series of patients prophylactically converted to an extended schedule of carboplatin administration after approximately 8 cycles of treatment. The objective of this retrospective study was to determine whether the extended schedule of carboplatin administration was associated with a lower rate of HSRs compared to the standard schedule in sequentially treated patients at Memorial Sloan-Kettering Cancer Center (MSKCC).

Section snippets

Methods

We performed a comprehensive retrospective electronic medical record review of patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer who received retreatment with carboplatin for recurrent disease between January 1998 and December 2008. Approval from the MSKCC Institutional Review Board was obtained. To identify patients who received second-line or greater carboplatin treatment, the pharmacy database was examined for patients who had received at least one partial dose

Results

We identified 715 patients who received retreatment with second-line or greater carboplatin at our center between January 1998 and December 2008. Eight patients (1.1%) were excluded from the analysis—7 had a history of preexisting carboplatin allergy and 1 had a prior history of cisplatin allergy.

Of the remaining 707 patients, 117 (16%) had a documented carboplatin HSR during second-line or greater carboplatin-based treatment. Characteristics of this cohort are listed in Table 2. The median age

Discussion

To date, platinum compounds remain the most active agents for recurrent platinum-sensitive ovarian cancer [8]. Carboplatin HSR is rarely (< 1% of patients) seen during the first course of carboplatin treatment [9]. This risk, however, rises considerably with increased platinum exposure [1], [10]. Clinical manifestations of carboplatin HSR, such as skin rash, flushing, itching, and abdominal cramping, usually resolve quickly following administration of antihistamines and steroids [11]. However,

Conclusion

Retreatment with carboplatin for women with recurrent platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancer was associated with a 17% incidence of grade 2 or worse carboplatin HSRs. Patients who received all carboplatin retreatment by 3-hour infusion after a lifetime total of 8 cycles of carboplatin appear to have had a lower risk of HSRs and received more total lifetime cycles of carboplatin before HSR developed. The contribution of the extended schedule versus the

Conflict of interest statement

1. Roisin O'Cearbhaill: no conflicts of interest to declare

2. Qin Zhou, MA: no conflicts of interest to declare

3. Alexia Iasonos, PhD: no conflicts of interest to declare

4. Martee L. Hensley, MD: no conflicts of interest to declare

5. Carol Aghajanian, MD: no conflicts of interest to declare

6. David R. Spriggs, MD: receives funding from Bristol Myers Squibb

7. Stuart M. Lichtman, MD: no conflicts of interest to declare

8. William P. Tew, MD: no conflicts of interest to declare

9. Paul Sabbatini,

References (25)

M. Navo et al.
Evaluation of the incidence of carboplatin hypersensitivity reactions in cancer patients
Gynecol. Oncol.
(2006)
J.R. Schwartz 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)
J.S. Morgan et al.
Hypersensitivity reactions to carboplatin given to patients with relapsed ovarian carcinoma
Eur. J. Cancer
(1994)
A. Trotti et al.
CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment
Semin. Radiat. Oncol.
(2003)
H.H. Windom et al.
Anaphylaxis to carboplatin—a new platinum chemotherapeutic agent
J. Allergy Clin. Immunol.
(1992)
M. Markman
Hypersensitivity reactions to carboplatin
Gynecol. Oncol.
(2002)
M.C. Castells et al.
Hypersensitivity reactions to chemotherapy: outcomes and safety of rapid desensitization in 413 cases
J. Allergy Clin. Immunol.
(2008)
D.S. Dizon et al.
Analysis of patients with epithelial ovarian cancer or fallopian tube carcinoma retreated with cisplatin after the development of a carboplatin allergy
Gynecol. Oncol.
(2002)
P.E. Hesterberg et al.
Risk stratification for desensitization of patients with carboplatin hypersensitivity: clinical presentation and management
J. Allergy Clin. Immunol.
(2009)
H. Gelderblom et al.
Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation
Eur. J. Cancer
(2001)

A. Gadducci et al.

Analysis of the pattern of hypersensitivity reactions in patients receiving carboplatin retreatment for recurrent ovarian cancer

Int. J. Gynecol. Cancer

(2008)

Cited by (42)

Outpatient desensitization of patients with moderate (high-risk) to severe platinum hypersensitivity reactions
2019, Gynecologic Oncology
Platinum hypersensitivity reactions (HSR) affect approximately 5% of the general oncologic population. Here we report the efficacy and safety of outpatient platinum desensitization protocol (PD) in gynecologic oncology patients with moderate (high-risk) to severe platinum HSR.
This is a retrospective report of patients with gynecologic malignancies undergoing an outpatient PD for moderate (high-risk) to severe platinum HSR from 2011 to 2017. Patient demographics, chemotherapy histories, and PD outcomes were collected. Descriptive statistics were performed given the exploratory nature of the study.
Forty-eight patients meeting inclusion criteria were identified. Most patients were being treated for ovarian cancer (56.3%) and were receiving carboplatin during their initial platinum HSR (75.0%). Patients received a mean of 10.3 platinum doses prior to their initial HSR. Transient hypertension was the most common sign of moderate (high-risk) HSR while persistent tachycardia was the most common sign of severe HSR. A total of 295 PD cycles were attempted with a successful completion rate of 96.6%. The mean number of PD cycles received by patients was 5.1. Almost 65% of patients experienced breakthrough reactions but over 58% of these breakthrough reactions were isolated to the first PD cycle. Only 8.3% of patients had severe breakthrough reactions, all of whom initially underwent shortened desensitization. Of these 4 patients, 2 successfully underwent desensitization with a prolonged protocol.
Outpatient PD is safe and effective in patients with gynecologic malignancies. This may present a feasible option for institutions with multi-disciplinary teams experienced with the management of platinum HSR.
Prophylactic 3-hour graduated infusion schedule minimizes risk of carboplatin hypersensitivity reactions - A prospective study
2018, Gynecologic Oncology
Citation Excerpt :
The long desensitization protocol method is highly efficacious and safe, but it is time consuming and expensive [14–17]. In a retrospective study, including 707 patients with platinum sensitive EOC and related cancers retreated with carboplatin over a 10-year period, O'Cearbhaill et al. concluded that fewer HSRs were recorded when the chemotherapy was administered as a prophylactic 3-hour graduated infusion compared to those receiving a standard 30-minute infusion (3% vs. 21%, P = 0.001) [18]. Aim of the present study was observation of HSR frequency, using the prophylactic 3-hour graduated infusion protocol with appropriate premedication in a prospective setting in patients with gynecological cancer receiving carboplatin retreatment in second line or above.
Aim of this study was observation of hypersensitivity reaction (HSR) frequency by using a 3-hour graduated infusion protocol with appropriate premedication as a prophylactic measure in patients with gynecological cancer receiving carboplatin retreatment in second line or above. None of the patients had experienced HSRs to platinum previously.
All the patients in this study received premedication with corticosteroids and anti-histamines followed by carboplatin as 3-hour graduated infusion. Carboplatin was administered either as monotherapy or in combination with other chemotherapeutic agents.
Ninety-nine patients with ovarian (n = 71), fallopian tube (n = 9), peritoneal (n = 9) and other gynecological cancers (5 uterine cancer, 5 abdominal cancer of gynecological origin) were retreated by a total of 611 cycles of carboplatin administered as monotherapy (210 cycles) or combination regime (401 cycles). HSRs were recorded in only 11 cycles (1.8%) in a total of 11 patients. While 8 of these patients had grade 1or 2 reactions (8.1%), only 3 patients had grade 3 reactions (3%). After pause in the infusion and complete resolution of HSR symptoms, an attempt of retreatment using this infusion protocol with extra premedication was successful in 6 of these patients without any reoccurrence of HSRs.
In this prospective study, we report that prophylactic 3-hour graduated infusion rate with appropriate premedication is associated with low frequency of HSRs in gynecological cancer patients requiring carboplatin retreatment in second line or above.
Outpatient desensitization in selected patients with platinum hypersensitivity reactions
2017, Gynecologic Oncology
Citation Excerpt :
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.
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.
Cisplatin can be safely administered to ovarian cancer patients with hypersensitivity to carboplatin
2017, Gynecologic Oncology
Hypersensitivity reactions (HSR) are frequently reported in patients rechallenged with carboplatin for recurrent ovarian cancer (ROC) and represent a critical issue, since discontinuation of the platinum-based therapy could affect prognosis. Several strategies to allow platinum rechallenge have been described, with controversial outcomes. The aim of this study is to illustrate a 10-year experience with cisplatin in patients with a previous HSR to carboplatin or at risk for allergy.
A retrospective review of all patients with platinum sensitive ROC retreated with carboplatin was performed between January 2007 and May 2016 at the Istituto Nazionale Tumori, Fondazione “G. Pascale”, Naples.
Among 183 patients, 49 (26.8%) presented HSR to carboplatin, mainly during second line therapy. Mean number of cycles before HSR was 8 (range 3–17). G2, G3 and G4 reaction were detected in 83%, 15% and 2% of patients, respectively. In a multivariate analysis including age, hystotype, BRCA status, previous known HSR, and combination drug administered, only the type of carboplatin-based doublet used as 2nd line therapy was found to significantly affect HSR development, with a protective effect of PLD (pegylated liposomal doxorubicin) (p = 0.014, OR = 0.027). Thirty seven patients (77%) with a previous HSR to carboplatin were rechallenged with cisplatin. Treatment was generally well tolerated. 5 patients (13.1%) experienced mild HSR to cisplatin, successfully managed in all cases. 14 patients were treated with cisplatin even without a carboplatin-related HSR due to other allergies. Among these, only one developed HSR (7.1%).
Cisplatin rechallenge is a feasible approach in patients experiencing HSR to carboplatin to maintain the beneficial effect of platinum while reducing hypersensitivity-related risks.
Extended carboplatin infusion does not reduce frequency of hypersensitivity reaction at initiation of retreatment in patients with recurrent platinum-sensitive ovarian cancer
2017, Journal of Allergy and Clinical Immunology: In Practice
Trabectedin as a chemotherapy option for patients with BRCA deficiency
2016, Cancer Treatment Reviews
Citation Excerpt :
Overall, these data prospectively confirmed that the signature of “repeated platinum sensitivity” identifies patients highly responsive to trabectedin, comparable to what obtained using platinum compounds. Consequently, trabectedin may represent a valuable option in patients who present contraindication or are unable to receive platinum which may impact more than 40% of patients at platinum reintroduction [36]. Furthermore, activity of trabectedin with respect to BRCA mutational status was also analyzed.
Trabectedin is a marine-derived product that was originally isolated from the Caribbean sea squirt Ecteinascidia turbinata and the first anticancer marine drug to be approved by the European Union. It is currently used as a single agent for the treatment of patients with soft tissue sarcoma after failure of anthracyclines and ifosfamide, or for those patients who are unsuited to receive these agents, and in patients with relapsed, platinum-sensitive ovarian cancer in combination with pegylated liposomal doxorubicin. Trabectedin has a unique multi-faceted mechanism of action that involves transcription regulation and DNA repair systems, including transcription-coupled nucleotide excision repair and homologous recombination repair (HRR) as the main hallmarks of its antiproliferative activity. In addition, trabectedin has shown the ability to modulate the tumor microenvironment. Indeed, the activity of trabectedin is related to altered function and expression of DNA repair genes, such as BRCA1 (BReast-CAncer susceptibility gene 1) and BRCA2. The particular sensitivity of sarcoma, ovarian and breast cancer cells deficient in HRR, previously observed in preclinical models, now has been confirmed in the clinical setting as well, suggesting that BRCA mutations are associated with improved clinical responses to trabectedin. Current efforts are focused on the evaluation of these unique features of trabectedin and on the identification of predictive factors for patients with an objective to determine whether a deficiency of HRR DNA repair pathway could impact the clinical benefit achieved from trabectedin.

View all citing articles on Scopus

¹: Dr. Spriggs receives research funding from Bristol Myers Squibb.

View full text

The prophylactic conversion to an extended infusion schedule and use of premedication to prevent hypersensitivity reactions in ovarian cancer patients during carboplatin retreatment

Abstract

Objective

Methods

Results

Conclusion

Introduction

Section snippets

Methods

Results

Discussion

Conclusion

Conflict of interest statement

Gynecol. Oncol.

Gynecol. Oncol.

Eur. J. Cancer

Semin. Radiat. Oncol.

J. Allergy Clin. Immunol.

Gynecol. Oncol.

J. Allergy Clin. Immunol.

Gynecol. Oncol.

J. Allergy Clin. Immunol.

Eur. J. Cancer

Analysis of the pattern of hypersensitivity reactions in patients receiving carboplatin retreatment for recurrent ovarian cancer

Int. J. Gynecol. Cancer