Toradol (ketorolac)
Perioperative use of ketorolac (Toradol,) in cancer surgery has shown promising results in improving patient outcomes, particularly in terms of reducing cancer recurrence and improving survival rates. Here's a comprehensive overview of the current evidence:
Potential Benefits
Improved Survival Rates
Several studies have found associations between perioperative ketorolac use and improved survival outcomes in cancer patients:
In breast cancer surgery, ketorolac administration just before the first incision was associated with a five-fold decrease in expected breast cancer recurrence events in the two years following surgery[2].
A meta-analysis found that perioperative NSAID use, including ketorolac, was associated with longer disease-free survival (HR = 0.84) and overall survival (HR = 0.78) in cancer surgery patients[4].
For ovarian cancer specifically, a study showed a favorable association between intraoperative ketorolac use and postoperative cancer progression[5].
Mechanism of Action
The potential anticancer effects of ketorolac are thought to be mediated through several mechanisms:
1. Anti-inflammatory effects: Ketorolac may block the "grow" signals triggered by surgical trauma, which could otherwise stimulate dormant cancer cells[2].
2. Inhibition of prostaglandin production: NSAIDs like ketorolac inhibit cyclooxygenase (COX) enzymes, reducing prostaglandin production which has been linked to various oncological events[4].
3. Reduction of angiogenic factors: Studies have shown that NSAIDs can decrease the production of factors that promote blood vessel growth in tumors[4].
Optimal Usage
Timing
The timing of ketorolac administration appears to be crucial:
In breast cancer surgery, the most significant benefits were observed when ketorolac was administered just before the first surgical incision[2].
For head and neck free flap reconstruction, a 15-mg dose of ketorolac was given intraoperatively at the time of microanastomosis and every 6 hours thereafter for a maximum of 5 days[6].
Dosage
The optimal dosage may vary depending on the specific procedure and patient factors:
In breast cancer surgery, doses of 20 or 30 milligrams were suggested, depending on patient size[2].
For head and neck surgery, a lower dose of 15 mg was found to be effective for pain relief while potentially reducing systemic morbidity[6].
Considerations and Precautions
While the potential benefits of perioperative ketorolac are promising, there are some important considerations:
Bleeding risk: As with all NSAIDs, ketorolac can increase the risk of bleeding. However, in many cancer surgeries, this risk may be outweighed by the potential benefits[2].
Patient selection: Ketorolac may not be suitable for all patients. Those with a history of bleeding disorders, kidney problems, high blood pressure, or gastrointestinal ulceration may not be candidates for ketorolac use[2].
Cancer type: The benefits of perioperative ketorolac appear to be more pronounced in certain cancer types, particularly breast and ovarian cancers[4].
Conclusion
The use of perioperative ketorolac in cancer surgery shows promise in improving long-term outcomes for patients. However, it's important to note that while the evidence is encouraging, much of it comes from retrospective studies and meta-analyses. Further prospective, randomized controlled trials are needed to definitively establish the optimal regimen and patient selection criteria for perioperative ketorolac use in cancer surgery[4].
Given the potential benefits and relatively low risk in carefully selected patients, discussing the use of perioperative ketorolac with your surgeon may be worthwhile for patients undergoing cancer surgery, particularly for breast or ovarian cancer[2][4][5].
Citations:
[2] https://www.oregonio.com/news/the-lifesaving-drug-your-breast-cancer-surgeon-may-not-be-using/
[3] https://www.sciencedirect.com/science/article/pii/S0007091217306311
[4] https://link.springer.com/article/10.1007/s11912-021-01133-8
Research
Tohme S, Simmons RL, Tsung A. Surgery for Cancer: A Trigger for Metastases. Cancer Res. 2017;77(7):1548–1552.
Hudson LG, Cook LS, Grimes MM, et al. Dual Actions of Ketorolac in Metastatic Ovarian Cancer. Cancers. 2019;11(8):1049.
Guo Y, Kenney SR, Cook L, et al. A Novel Pharmacologic Activity of Ketorolac for Therapeutic Benefit in Ovarian Cancer Patients. Clin. Cancer Res. 2015;21(22):5064–5072.
Guo Y, Kenney SR, Muller CY, et al. R-Ketorolac Targets Cdc42 and Rac1 and Alters Ovarian Cancer Cell Behaviors Critical for Invasion and Metastasis. Mol. Cancer Ther. 2015;14(10):2215–2227.
Forget P, Bentin C, Machiels J-P, et al. Intraoperative use of ketorolac or diclofenac is associated with improved disease-free survival and overall survival in conservative breast cancer surgery. Br. J. Anaesth. 2014;113:i82–i87.
Desmedt C, Demicheli R, Fornili M, et al. Potential Benefit of Intra-operative Administration of Ketorolac on Breast Cancer Recurrence According to the Patient’s Body Mass Index. JNCI: J. Natl. Cancer Inst. 2018;110(10):1115–1122.
How does ketorolac compare to other NSAIDs in cancer treatment
Based on the available evidence, ketorolac appears to have some unique advantages compared to other NSAIDs for perioperative use in cancer surgery:
1. Stronger anti-cancer effects:
Ketorolac has shown more pronounced benefits for cancer outcomes compared to other NSAIDs in some studies. A meta-analysis found that while perioperative NSAID use in general was associated with improved disease-free and overall survival, ketorolac specifically showed a significant benefit for overall survival (HR = 0.63)[5].
2. Novel mechanism of action:
Unlike other NSAIDs that primarily work through COX inhibition, ketorolac has a unique pharmacological property. Its R-enantiomer inhibits the small GTPases Rac1 and Cdc42, which are relevant tumor targets[2]. This dual mechanism may contribute to its anti-cancer effects.
3. Timing and dosage:
Studies suggest that a single dose of ketorolac given just before surgical incision can have significant benefits. For breast cancer surgery, this approach was associated with a five-fold decrease in expected cancer recurrence events in the two years following surgery[3].
4. Potency:
Ketorolac is considered a strong analgesic compared to many other NSAIDs. It provides relief from mild to severe pain in the majority of patients and has similar analgesic efficacy to opioids in many cases[1].
5. Opioid-sparing effects:
Ketorolac has been shown to reduce opioid requirements by 25-50% when used perioperatively, which can lead to fewer opioid-related side effects[1].
However, it's important to note some limitations:
1. Bleeding risk:
Ketorolac may carry a higher risk of gastrointestinal bleeding compared to some other NSAIDs. One study found it to be 5 times more gastrotoxic than other NSAIDs[7].
2. Short-term use:
The benefits of ketorolac seem to be most pronounced with short-term perioperative use. Prolonged use (>5 days) is associated with increased risk of adverse events[1].
3. Patient selection:
Ketorolac may not be suitable for all patients, particularly those with a history of bleeding disorders, kidney problems, or gastrointestinal ulceration[3].
In conclusion, while ketorolac shows promise in cancer surgery, particularly for its potential anti-cancer effects, it should be used judiciously, considering its risk profile. The decision to use ketorolac should be made on a case-by-case basis, weighing the potential benefits against the risks for each individual patient.
Citations:
[1] https://pubmed.ncbi.nlm.nih.gov/9010653/
[3] https://www.oregonio.com/news/the-lifesaving-drug-your-breast-cancer-surgeon-may-not-be-using/
[4] https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD013263.pub2/full
[5] https://link.springer.com/article/10.1007/s11912-021-01133-8
[6] https://academic.oup.com/painmedicine/article/2/4/336/1877017?login=false
[7] https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/190886