Impact of carboplatin hypersensitivity and desensitization on patients with recurrent ovarian cancer.
PURPOSE
Hypersensitivity reactions (HSRs) to chemotherapy is an ongoing issue in cancer treatments. Strategies to induce tolerance and maximize chemotherapy efficacy include desensitization protocols. The precise impact of these protocols, however, in the long-term treatments remains unclear. We aim to compare overall survival (OS) in hypersensitive patients treated with carboplatin desensitization to patients without hypersensitivity reactions. We also sought to identify new risk factors for HSRs and reconfirm that the DNA repair enzyme, germline BRCA1/2 (gBRCA1/2), is a risk factor for hypersensitivity.


EXPERIMENTAL DESIGN
Retrospective study in patients with ovarian cancer tested for gBRCA1/2 mutations who received more than six infusions of carboplatin from August 2005 to November 2016. Two-sided Fisher exact, Student's t test and Gehan-Breslow-Wilcoxon test were used for statistical analysis. Univariate and multivariate analyses were completed to identify independent predictors of survival. Statistical significance was set with a two-sided p value of 0.05.


RESULTS
Ninety-one patients with gBRCA1/2 testing met inclusion. Forty patients (44%) were gBRCA1/2-deficient and 51 (56%) were gBRCA1/2-proficient. Patients with gBRCA1/2 deficiencies had a higher likelihood of developing carboplatin hypersensitivity, HR 6.433 (95% CI: 1.868-22.149). None of the patients with carboplatin hypersensitivity were given PARP inhibitors prior to the development of HSRs. The patients with recurrent advanced stage (III-IV) ovarian cancer had a higher likelihood of developing carboplatin hypersensitivity, HR 4.783 (1.008-22.689). Moreover, we found that hypersensitive patients who underwent carboplatin desensitization had a 48-month longer OS than patients without hypersensitivity to carboplatin not undergoing carboplatin desensitization (p = 0.0094). A subgroup analysis indicated that gBRCA1/2-proficient hypersensitive patients undergoing carboplatin desensitization had a 43-month longer OS than gBRCA1/2-proficient patients without HSRs (p = 0.034).


CONCLUSIONS
We confirmed that gBRCA1/2 deficiency and advanced stage are independent risk factors for development of carboplatin hypersensitivity in ovarian cancer patients. Our study also shows improved OS in hypersensitive patients receiving CD compared to non-hypersensitive patients, independent of gBRCA1/2.
['Altwerger|Gary|G|http://orcid.org/0000-0002-2252-947X', 'Florsheim|Esther B|EB|', 'Menderes|Gulden|G|', 'Black|Jonathan|J|', 'Schwab|Carlton|C|', 'Gressel|Gregory M|GM|', 'Nelson|Wendelin K|WK|', 'Carusillo|Nina|N|', 'Passante|Terri|T|', 'Huang|Gloria|G|', 'Litkouhi|Babak|B|', 'Azodi|Masoud|M|', 'Silasi|Dan-Arin|DA|', 'Santin|Alessandro|A|', 'Schwartz|Peter E|PE|', 'Ratner|Elena S|ES|']
D000328:Adult D000368:Aged D000369:Aged, 80 and over D000970:Antineoplastic Agents D019313:BRCA1 Protein D016190:Carboplatin D004249:DNA Damage D003888:Desensitization, Immunologic D004342:Drug Hypersensitivity D005260:Female D006801:Humans D008875:Middle Aged D009367:Neoplasm Staging D010051:Ovarian Neoplasms D016016:Proportional Hazards Models D012008:Recurrence
Carboplatin hypersensitivity Ovarian cancer Overall survival Carboplatin desensitization BRCA DNA damage