Data from a retrospective analysis, recently presented at the Society of Gynecologic Oncology's (SGO) 2017 Annual Meeting on Women's Cancer, found that treatment with a carboplatin desensitization regimen led to improved overall survival in BRCA-proficient patients with ovarian cancer (Poster Session 237).
Considered a standard-of-care treatment for ovarian cancer, carboplatin induces tumor cell death by DNA double-strand breaks. Such double-strand breaks activate DNA repair mechanisms, including the BRCA homologous recombination repair enzymes.
However, after exposure to multiple cycles of carboplatin therapy, hypersensitivity reactions can occur. “Hypersensitivity can prove dangerous, even life-threatening,” noted Gary H. Altwerger, MD, study author and a Gynecologic Oncology Fellow at Yale University School of Medicine, New Haven, Conn. “Recognizing that carboplatin is the best agent for platinum-sensitive ovarian cancer, our team set out to develop desensitization protocols that can quickly and efficiently prevent hypersensitivity reactions.”
Poster Session 237
Following the development of the carboplatin desensitization protocol by a team of pharmacists, physician assistants, and gynecologic oncologists at Yale, the team sought to conduct a retrospective analysis to determine its effectiveness among patients with ovarian cancer.
“This study was built upon the need to understand patient overall survival with this carboplatin desensitization protocol, as well as to determine if patients had increased hypersensitivity if they had BRCA mutations,” Altwerger said.
Utilizing the institution's EHR database, researchers conducted a search for ovarian cancer patients who were tested for BRCA mutations between 2005 and 2016. Other inclusion criteria included patients with at least six infusions of carboplatin and those who had a hypersensitivity reaction; positive intradermal skin tests were also used as inclusion criteria for the retrospective study.
“As a part of management during recurrence, patients will automatically have an intradermal skin test prior to the start of the patients' seventh total cycle,” explained Altwerger. “Patients who tested positive were enrolled in the desensitization protocol.”
Patients who had previously received PARP inhibitors were not included in the analysis of the study. Adverse events were graded using common terminology criteria. Hypersensitive reactions were graded on a scale of 0 to 5, from no reaction (0) to mild/moderate (1-2) to severe/life-threatening (3-5), according to Altwerger.
All cases included treatment with carboplatin, and all patients were evaluated for hypersensitivity during the seventh cycle of therapy and beyond. The study included 40 BRCA-deficient and 51 BRCA-proficient patients with ovarian cancer.
“Also, it is important to note there were no differences in BMI, age, optimal cytoreductive surgery, the number of platinum agents cycles, or the number of chemotherapy regimens after platinum agents between the patient groups,” Altwerger said.
Researchers reported a median overall survival of 127 months for the entire study population, as well as 5- and 10-year overall survival of 72 percent and 51 percent, respectively.
Data found median overall survival was significantly improved for patients with BRCA deficiency compared to the BRCA-proficient group (176 months vs. 83 months; P=.0249). “Interestingly, patients with carboplatin hypersensitivity and carboplatin desensitization had a 48-month longer survival rate compared to those without hypersensitivity reactions (131 months vs. 83 months),” reported Altwerger. “It is possible that the prolonged overall survival observed in hypersensitive patients was owed to gBRCA1/2 deficiencies. However, in the BRCA-proficient group, patients with hypersensitivity had a median overall survival of 114 while those without carboplatin hypersensitivity had a survival rate of 71 months.
“This means that the improved overall survival found in hypersensitive patients was independent of gBRCA1/2 status,” he continued. “This was an interesting finding because when we initiated this study we were unsure whether or not carboplatin hypersensitivity and carboplatin desensitization would have any effect on overall survival.
“In addition to the increased overall survival in hypersensitive patients treated with carboplatin desensitization, we also found that patients with gBRCA1/2 deficiencies were more susceptible to develop hypersensitivity reactions when treated with carboplatin, suggesting that gBRCA1/2 is a risk factor for chemotherapy hypersensitivity.”
Seventy-eight percent (31/40) of patients with gBRCA1/2 deficiencies were found to have a carboplatin hypersensitivity reaction. “The odds of a carboplatin hypersensitive patient testing positive for a germline BRCA mutation were 5.3 times that of a patient without carboplatin hypersensitivity,” emphasized Altwerger.
“Patients with BRCA mutations treated with carboplatin may be at increased risk of developing hypersensitive reactions,” researchers concluded. “This finding suggests a link between carboplatin-induced DNA damage and hypersensitive reactions.”
Altwerger acknowledged the study design is a limitation. “Like any retrospective study, there will always be the possibility of confounders that researchers cannot identify,” he noted. “While we did our best to eliminate such confounders, there can be bias, and for that, a randomized controlled trial is required.”
Another potential limitation to keep in mind was the selection criteria. The selection criteria likely contributed to the very long overall survival in all patient groups. “We selected patients that had received more than six cycles of carboplatin since hypersensitivities typically occur at that time,” Altwerger clarified. “The patients excluded had discontinued carboplatin prior to completion of six cycles due to progressive disease, treatment failure, poor follow-up, and/or medical complications. This study was, therefore, bias toward including patients who did well with carboplatin therapy, both from a tumor response and medical tolerability perspectives, so it was expected that these patients would have a better tumor response compared to other cohorts.”
Impact on Practice
This retrospective analysis supports the use of carboplatin desensitization protocols in ovarian cancer patients who are hypersensitive to carboplatin.
“This study shows that carboplatin desensitization is not detrimental to hypersensitive patients and perhaps improves their overall survival,” Altwerger explained. “And so, this data advocates for the continued use of platinum therapy in light of a carboplatin hypersensitivity.
“This is the most significant practice implication from our analysis,” he continued. “Utilizing desensitization protocols is critical for ovarian cancer patients because it is the most effective treatment available.”
Another finding to consider in clinical practice is the higher rate of carboplatin hypersensitivity among BRCA-deficient patients, noted Altwerger. “While this data requires further study to understand the reasons behind this trend, it could be utilized as a risk factor to identify if patients may develop a hypersensitivity in the future.”
Additional studies are necessary to further understand the mechanisms behind the data uncovered during this retrospective analysis.
“It is important to determine the role of DNA damage in the development of hypersensitivity reactions to chemotherapy,” Altwerger noted. “Additionally, it is necessary to understand why patients have better outcomes when they have hypersensitivity reactions and carboplatin desensitization.
“Is it the protocol itself?” he queried. “Do the medications utilized improve the response of the tumor to carboplatin? Or, is there something inherently different in the patients' immune systems that improves tumor response to carboplatin in these hypersensitive patients?”
The answers to these questions, which could improve practices in the future, require ongoing research, Altwerger said. “This is difficult to parse in a case control study and can really be sussed out in a lab,” he concluded. “We must continue to dig deeper to understand the mechanism behind carboplatin hypersensitivity to ensure our patients receive the best possible care.”
Catlin Nalley is associate editor.