Cancer metastasis : an anti-inflammatory drug called ketorolac can promote long-term survival

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An anti-inflammatory drug called ketorolac, given before surgery, can promote long-term survival in animal models of cancer metastasis, a team of scientists has found.

Furthermore, so-called “pro-resolution” therapies can also trigger the immune system to eliminate metastatic cells.

The research also suggests that flanking chemotherapy with anti-inflammatory drugs can unleash anti-tumor immunity.

The findings, published in Journal of Clinical Investigation, also provide a mechanistic explanation for the anti-metastatic effects of ketorolac, previously observed in human breast cancer surgery.

Vikas P. Sukhatme, MD, ScD, dean of Emory University School of Medicine, is senior author of the paper.

He was previously at Beth Israel Deaconess Medical Center and Harvard Medical School, with lead authors Dipak Panigrahy, MD and Allison Gartung, PhD.

“Collectively, our findings suggest a potential paradigm shift in our approach to resectable cancers,” says Sukhatme.

“Clinical trials are now urgently needed to validate these animal studies.”

Most cancer-related deaths come from metastases, the spread of cancer cells from a primary tumor to surrounding tissues or distant organs.

The cells that seed metastases are often in microscopic clusters – a surgeon can’t see them.

Chemotherapy, typically given after or prior to surgery is aimed at eradicating these cancer cells in the hopes of preventing cancer recurrence.

However, chemotherapy can sometimes stir up inflammation, promoting metastasis.

Credit: Emory University
“Cancer therapy is a double-edged sword,” says Panigrahy.

“Surgery and chemotherapy can induce an inflammatory or immunosuppressive injury response that promotes dormant metastatic cells to start proliferating, leading to tumor recurrence.”

Ketorolac is an inexpensive NSAID (nonsteroidal anti-inflammatory drug).

Because of concern over side effects, it is only approved by the FDA for short-term pain management “at the opioid level.”

It differs from other NSAIDs in that it preferentially inhibits the enzyme COX-1, more than COX-2.

Other studies of prevention of cancer recurrence have focused on COX-2 inhibitors.

In the paper, the researchers show that preoperative, but not postoperative, ketorolac administration (as it typically is currently used), can eradicate cancer metastasis in mouse models and extend survival of animals.

The effects appear to depend on COX-1 inhibition, because other NSAIDS did not display the same survival benefits.

A further increase in the percentage of animals that survived following resection of the primary tumor was noted when ketorolac was combined with low dose aspirin and omega 3 fatty acids.

Of note, resolvins, metabolic products of omega 3 fatty acids that accelerate the resolution of inflammation, also gave similar effects.

The researchers gained insight into how these approaches could be combined with other anti-cancer therapies.

Ketorolac and the resolvins appear to indirectly stimulate T cells, part of the immune system, augmenting the action of immunotherapies such as checkpoint inhibitors, but conflicting with chemotherapy.

The authors conclude: “…we and others are showing that it may be possible to eradicate micrometastatic disease and dormant tumor cells without chemotherapy.

Here, we demonstrate that unleashing T cell immunity by preoperative suppression of systemic inflammation or stimulation of inflammation resolution exhibits potent antitumor activity, even curing mice of micrometastases” which are largely responsible for cancer recurrence following surgery.



Nonsteroidal anti-inflammatory drugs (NSAIDs) are currently used in some countries as analgesics in primary cancer surgery. Retrospective studies suggest that NSAIDs could reduce breast cancer recurrences.

Because NSAIDs also act on biological mechanisms present in patients with increased adiposity, we aimed at assessing whether the intra-operative administration of ketorolac or diclofenac would be associated with a reduction of recurrence in patients with elevated body mass index (BMI).

METHODS:

We considered two institutional retrospective series of 827 and 1007 patients evaluating the administration of ketorolac (n = 529 with, n = 298 without) or diclofenac (n = 787 with, n = 220 without).

The BMI subgroups were defined as less than 25 kg/m2 (lean) and 25 or more kg/m2 (overweight and obese). Cumulative incidence estimation of distant metastases as well as Fine-Gray and Dixon-Simon models was used. These analyses were adjusted for clinico-pathological variables. All statistical tests were two-sided.

RESULTS:

The administration of ketorolac was statistically significantly associated with decreased incidence of distant recurrences (adjusted hazard ratio [aHR]= 0.59, 95% confidence interval [CI] = 0.37 to 0.96, P = .03).

In particular, the association was evident in the high-body mass index (BMI) group of patients (aHR = 0.55, 95% CI = 0.31 to 0.96, P = .04). The administration of diclofenac was not statistically significantly associated with decreased incidence of distant recurrences, either in the global population or in the BMI subgroups.

CONCLUSIONS:

These results show that the intra-operative administration of ketorolac, but not diclofenac, is statistically significantly associated with a reduction of distant recurrences in patients with increased BMI.

Altogether, this study points to a potentially important repositioning of ketorolac in the intra-operative treatment of patients with elevated BMI that, if prospectively validated, might be as impactful as and cheaper than adjuvant systemic anticancer therapies.

PMID: 29718396 DOI: 10.1093/jnci/djy042


More information: Dipak Panigrahy et al. Preoperative stimulation of resolution and inflammation blockade eradicates micrometastases, Journal of Clinical Investigation (2019). DOI: 10.1172/JCI127282

Journal information: Journal of Clinical Investigation
Provided by Emory University

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