Ketorolac may reduce breast cancer recurrence risk, particularly in overweight patients

 

Ketorolac administered during primary tumor surgery may cut risk of distant recurrences in patients with breast cancer, results of a retrospective study show.

Overweight patients appeared most likely to benefit from interoperative treatment with this nonsteroidal anti-inflammatory drug, study investigators reported.

“This approach could be extremely appealing for parts of the globe where obesity has been strongly increasing during the last decade and where resources for cancer treatment are scarce,” they wrote. The report was published in the Journal of the National Cancer Institute.

Ketorolac inhibits enzymes upregulated by leptin, a hormone abnormally secreted in the setting of overweight or obesity, which might explain the concentration of benefit in high–body mass index individuals, noted Christine Desmedt, PhD, of the Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Brussels, and her coauthors.

Indeed, the study also showed no benefit to intraoperative administration of another NSAID, diclofenac, which does not appear to have the same enzyme-inhibitory effects as ketorolac, the investigators said.

This recently published analysis by Dr. Desmedt and her colleagues was based on two retrospective series of patients: one evaluating intraoperative ketorolac in 529 patients versus 298 patients who received no ketorolac, and one evaluating intraoperative diclofenac in 787 patients, versus 220 who did not receive that NSAID.

The investigators found a significant association between ketorolac given during surgery and decreased incidence of distant metastasis (adjusted hazard ratio [aHR], 0.59, 95% confidence interval, 0.37-0.96, P = .03). Reduced recurrence was most evident in patients with high BMI (aHR, 0.55; 95% CI, 0.31-0.96; P = .04).

 

Further evaluation revealed that the benefit of ketorolac was “clearly associated” with a reduction in early metastases, both overall and in the high-BMI subgroup, the investigators said.

By contrast, intraoperative diclofenac was not associated with a decrease in distant recurrences, overall (adjusted HR, 1.04; 95% CI, 0.58-1.87, P = .88) or in BMI subgroup analysis, investigators said.

While some might be surprised that a single dose of ketorolac could reduce distant recurrence, it might be explained by the timing of NSAID delivery, they noted. In previous studies, primary tumor removal has been shown to disturb disease homeostasis, and thus might trigger early recurrences.

“Complex system dynamics are exquisitely sensitive on initial conditions, and, therefore, changes occurring in critical early times may be able to cause major changes in system evolution,” the investigators wrote in a discussion of the results.

 

The finding is also not without precedent. The authors cited one Scandinavian randomized trial in which a single course of perioperative cyclophosphamide significantly improved disease-free survival at more than 17 years of follow-up; by contrast, giving the treatment 2-4 weeks after mastectomy provided no such benefit.

In addition, ketorolac’s potential perioperative benefit has been shown in other tumor types, including improved disease-free survival in one institutional series of lung cancer patients, and reduced disease-specific mortality in a retrospective study of ovarian cancer patients.

The present breast cancer study is limited because it is retrospective, and does not address questions regarding optimal timing or duration of dose. However, “it suggests a potentially important repositioning of ketorolac in the intraoperative treatment of breast cancer patients with elevated BMI, and points to the need for a prospective confirmatory randomized trial,” the authors said.

Dr. Desmedt and her colleagues reported no conflicts of interest related to the study.

SOURCE: Desmedt C et al. J Natl Cancer Inst. 2018 Apr 30. doi: 10.1093/jnci/djy042.

 

Ketorolac administered during primary tumor surgery may cut risk of distant recurrences in patients with breast cancer, results of a retrospective study show.

Overweight patients appeared most likely to benefit from interoperative treatment with this nonsteroidal anti-inflammatory drug, study investigators reported.

“This approach could be extremely appealing for parts of the globe where obesity has been strongly increasing during the last decade and where resources for cancer treatment are scarce,” they wrote. The report was published in the Journal of the National Cancer Institute.

Ketorolac inhibits enzymes upregulated by leptin, a hormone abnormally secreted in the setting of overweight or obesity, which might explain the concentration of benefit in high–body mass index individuals, noted Christine Desmedt, PhD, of the Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Brussels, and her coauthors.

Indeed, the study also showed no benefit to intraoperative administration of another NSAID, diclofenac, which does not appear to have the same enzyme-inhibitory effects as ketorolac, the investigators said.

This recently published analysis by Dr. Desmedt and her colleagues was based on two retrospective series of patients: one evaluating intraoperative ketorolac in 529 patients versus 298 patients who received no ketorolac, and one evaluating intraoperative diclofenac in 787 patients, versus 220 who did not receive that NSAID.

The investigators found a significant association between ketorolac given during surgery and decreased incidence of distant metastasis (adjusted hazard ratio [aHR], 0.59, 95% confidence interval, 0.37-0.96, P = .03). Reduced recurrence was most evident in patients with high BMI (aHR, 0.55; 95% CI, 0.31-0.96; P = .04).

 

Further evaluation revealed that the benefit of ketorolac was “clearly associated” with a reduction in early metastases, both overall and in the high-BMI subgroup, the investigators said.

By contrast, intraoperative diclofenac was not associated with a decrease in distant recurrences, overall (adjusted HR, 1.04; 95% CI, 0.58-1.87, P = .88) or in BMI subgroup analysis, investigators said.

While some might be surprised that a single dose of ketorolac could reduce distant recurrence, it might be explained by the timing of NSAID delivery, they noted. In previous studies, primary tumor removal has been shown to disturb disease homeostasis, and thus might trigger early recurrences.

“Complex system dynamics are exquisitely sensitive on initial conditions, and, therefore, changes occurring in critical early times may be able to cause major changes in system evolution,” the investigators wrote in a discussion of the results.

 

The finding is also not without precedent. The authors cited one Scandinavian randomized trial in which a single course of perioperative cyclophosphamide significantly improved disease-free survival at more than 17 years of follow-up; by contrast, giving the treatment 2-4 weeks after mastectomy provided no such benefit.

In addition, ketorolac’s potential perioperative benefit has been shown in other tumor types, including improved disease-free survival in one institutional series of lung cancer patients, and reduced disease-specific mortality in a retrospective study of ovarian cancer patients.

The present breast cancer study is limited because it is retrospective, and does not address questions regarding optimal timing or duration of dose. However, “it suggests a potentially important repositioning of ketorolac in the intraoperative treatment of breast cancer patients with elevated BMI, and points to the need for a prospective confirmatory randomized trial,” the authors said.

Dr. Desmedt and her colleagues reported no conflicts of interest related to the study.

SOURCE: Desmedt C et al. J Natl Cancer Inst. 2018 Apr 30. doi: 10.1093/jnci/djy042.

 

Ketorolac administered during primary tumor surgery may cut risk of distant recurrences in patients with breast cancer, results of a retrospective study show.

Overweight patients appeared most likely to benefit from interoperative treatment with this nonsteroidal anti-inflammatory drug, study investigators reported.

“This approach could be extremely appealing for parts of the globe where obesity has been strongly increasing during the last decade and where resources for cancer treatment are scarce,” they wrote. The report was published in the Journal of the National Cancer Institute.

Ketorolac inhibits enzymes upregulated by leptin, a hormone abnormally secreted in the setting of overweight or obesity, which might explain the concentration of benefit in high–body mass index individuals, noted Christine Desmedt, PhD, of the Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Brussels, and her coauthors.

Indeed, the study also showed no benefit to intraoperative administration of another NSAID, diclofenac, which does not appear to have the same enzyme-inhibitory effects as ketorolac, the investigators said.

This recently published analysis by Dr. Desmedt and her colleagues was based on two retrospective series of patients: one evaluating intraoperative ketorolac in 529 patients versus 298 patients who received no ketorolac, and one evaluating intraoperative diclofenac in 787 patients, versus 220 who did not receive that NSAID.

The investigators found a significant association between ketorolac given during surgery and decreased incidence of distant metastasis (adjusted hazard ratio [aHR], 0.59, 95% confidence interval, 0.37-0.96, P = .03). Reduced recurrence was most evident in patients with high BMI (aHR, 0.55; 95% CI, 0.31-0.96; P = .04).

 

Further evaluation revealed that the benefit of ketorolac was “clearly associated” with a reduction in early metastases, both overall and in the high-BMI subgroup, the investigators said.

By contrast, intraoperative diclofenac was not associated with a decrease in distant recurrences, overall (adjusted HR, 1.04; 95% CI, 0.58-1.87, P = .88) or in BMI subgroup analysis, investigators said.

While some might be surprised that a single dose of ketorolac could reduce distant recurrence, it might be explained by the timing of NSAID delivery, they noted. In previous studies, primary tumor removal has been shown to disturb disease homeostasis, and thus might trigger early recurrences.

“Complex system dynamics are exquisitely sensitive on initial conditions, and, therefore, changes occurring in critical early times may be able to cause major changes in system evolution,” the investigators wrote in a discussion of the results.

 

The finding is also not without precedent. The authors cited one Scandinavian randomized trial in which a single course of perioperative cyclophosphamide significantly improved disease-free survival at more than 17 years of follow-up; by contrast, giving the treatment 2-4 weeks after mastectomy provided no such benefit.

In addition, ketorolac’s potential perioperative benefit has been shown in other tumor types, including improved disease-free survival in one institutional series of lung cancer patients, and reduced disease-specific mortality in a retrospective study of ovarian cancer patients.

The present breast cancer study is limited because it is retrospective, and does not address questions regarding optimal timing or duration of dose. However, “it suggests a potentially important repositioning of ketorolac in the intraoperative treatment of breast cancer patients with elevated BMI, and points to the need for a prospective confirmatory randomized trial,” the authors said.

Dr. Desmedt and her colleagues reported no conflicts of interest related to the study.

SOURCE: Desmedt C et al. J Natl Cancer Inst. 2018 Apr 30. doi: 10.1093/jnci/djy042.