Reducing Risks of Infusion Related Reactions in Targeted Cancer Therapy
SummaryInfusion-related reactions occur with a wide variety of therapeutic agents used in the treatment of cancer but have become a particular concern of the targeted monoclonal antibody therapies. A post-hoc analysis performed on data from a recent large study suggests a way of minimising risk.
A simple means to help avoid the complication of infusion-related reactions (IRR) affecting patients receiving monoclonal antibody treatments, has been identified in MABEL, a major European open-label study of metastatic colorectal cancer (mCRC) patients who received third-line treatment with cetuximab (Erbitux) and irinotecan (Camptostar) (1). Adding a corticosteroid to antihistamine prophylaxis almost halved the number of reactions seen with cetuximab (50 vs 92). Cetuximab is an IgG1 recombinant chimeric monoclonal antibody that targets the epidermal growth factor receptor (EGFR) on the surface of tumours.
“The frequency of IRRs was lower in patients who received any antihistamine plus corticosteroids as prophylactic medication compared to patients who received only antihistamines (9.6% vs 25.6%)” noted the MABEL study authors led by oncologists Salvatore Siena of Milan, Italy and Robert Glynne-Jones of Mount Vernon Hospital, Middlesex, who presented data at the American Society of Clinical Oncology gastro-intestinal (ASCO-GI) cancers meeting in Orlando, Florida on 21st January. “A similar trend was seen for grade3/4 IRRs (1% vs 4.7%).”
The practice of using corticosteroids as well as antihistamines was shown to be more commonly applied in the UK and Ireland, where nine out of 10 patients received the prophylaxis, than in any of the other six European countries participating – Austria, Germany, France, Italy, Spain and Switzerland - where corticosteroid and anitihistamine prophylaxis rates ranged from 49 to 81 per cent.
The absolute numbers of any IRRs seen in the study were 108 among 422 patients receiving antihistamines without corticosteroids and 67 among 700 patients who received both antihistamines and corticosteroids. The figures for grade 3/4 IRR were 20 and 7 respectively. Use of chlorphenamine antihistamine treatment reduced the incidence of IRRs to a small extent compared to other antihistamines but did not match the benefit seen by adding a corticosteroid.
Of IRRs specifically related to cetuximab, there were 92 in the antihistamine- without-corticosteroid group but only 50 in the group who received dual prophylaxis. Although numbers are small the authors conclude: “These data suggest that pre-medication impacts on occurrence of IRRs and the addition of corticosteroids to antihistamines seems to reduce them.”
The 1147 patients participating in MABEL were treated with the EGFR inhibitor cetuximab plus irinotecan having previously failed irinotecan therapy alone. The primary and secondary objectives of the 48-week study were to investigate the combination’s effects on progression-free survival at 12-week intervals, to determine median overall survival after initiating treatment and to monitor toxicity. These data were presented at ASCO in 2006 (2). The effect of pre-medications on IRRs was a post-hoc analysis. The latter showed that type of prophylaxis used had no impact on progression-free or overall survival at any point over the two-year study. Median survival for patients taking either type of prophylaxis was 9.2 months. “This is comparable to the 8.6 months median survival reported by the pivotal BOND study,” commented the authors. BOND investigated the combination of cetuximab and irinotecan in a smaller number of patients treated in specialist oncology units. MABEL studied the same drug combination in 1147 patients in general hospitals to confirm that safety and efficacy observed in BOND is achievable in the wider community.
Severe (grade3/4) infusion reactions are listed as a warning on cetuximab data sheets which say they occurred in 2.5 to 3 per cent of patients studied in clinical trials of cetuximab in combination with irinotecan; of these, 90 per cent occurred with the first infusion. Reactions carry a rare risk of fatality (<1 per 1000). Prescribing advice however currently mentions only pre-medication with an H1 antagonist as prophylaxis.
Types of corticosteroid used in MABEL included budesonide, dexamethasone, hydrocortisone, prednisone and others, while antihistamines used included chlophenamine, alizapride, cetirizine, clemastine, promethazine, dexchlorpheniramine, diphenhydramine and dimentindene.
• A study from Memorial Sloan-Kettering Cancer Center (MSKCC) in New York, also presented at ASCO GI, observed 453 patients who received 50mg of diphenhydramine (Benadryl) prior to the first dose of cetuximab and 25 mg before the second dose (3). Seven patients (1.5%) developed grade 3 IRRs and 17 (4%) developed grade 1-2 IRRs linked in each case to the first cetuximab dose. The authors, led by Ki Chung, say that since IRRs are exceedingly rare beyond the first cetuximab dose and because antihistamines carry side effects, antihistamine prophylaxis after the first two doses doesn’t appear to be warranted. The policy adopted by MSKCC’s pharmacy and therapeutics committee is therefore to omit prophylaxis after two doses.
1. Siena S et al. MABEL – a large multinational study of cetuximab plus irinotecan in irinotecan-resistant metastatic colorectal cancer: update on infusion-related reactions (IRRs). ASCO 2007 GI Cancers Symposium Proceedings (abstr 238).
2. Wilke H et al. MABEL – a large multinational study of cetuximab plus irinotecan in metastatic colorectal cancer progressing on irinotecan. ASCO 2006 Abstract 3549.
3. Chung KY et al. Evaluation of routine antihistamine premedication after the first two doses of cetuximab. ASCO 2007 GI Cancers Symposium Proceedings (abstr 357).
Olwen Glynn Owen
Pharmiweb Field reporter