Preop Ketorolac Cuts Breast Cancer Recurrence

Janis C. Kelly

June 10, 2010

June 10, 2010 — Surgery to remove solid tumors can trigger metastatic spread. A groundbreaking analysis by Patrice Forget, MD, and colleagues from the Université catholique de Louvain, in Louvain-la-Neuve, Belgium, suggests that using different intraoperative analgesics for cancer surgery can reduce this risk.

We cannot ignore the possibility that anesthesia may contribute to the recurrence of cancer months or even years after cancer surgery.

An editorial by James G. Bovill MD, PhD, from Leiden University in the Netherlands, which accompanies the paper published in the June issue of Anesthesia & Analgesia, raises the broader question of whether inhaled anesthesia might trigger the growth of microscopic primary tumors even after surgery unrelated to cancer.

"Even though the evidence is inconclusive and at times conflicting, we cannot ignore the possibility that anesthesia may contribute to the recurrence of cancer months or even years after cancer surgery," Dr. Bovill writes in the editorial. "Less clear, but equally worrying, is the possibility that anesthesia could activate dormant cancer cells in an individual undergoing noncancer surgery, with the development of an overt cancer that otherwise might never have materialized in the lifetime of that individual," he adds.

Review of Mastectomy Patients

In the new analysis, the Belgian team, headed by Dr. Forget, reviewed the medical records of 327 consecutive patients who had undergone mastectomy with axillary dissection between February 2003 and September 2008.

All mastectomies were performed by the same surgeon and jointly followed by this surgeon and the same oncologist, who used chemotherapy, radiotherapy, and endocrine therapy in accordance with the 9th and 10th St. Gallen expert consensus guidelines.

The main objective of the study was to determine the effect, if any, of the administration of different intraoperative analgesics (sufentanil, ketamine, clonidine, and ketorolac) on cancer recurrence after mastectomy. The primary end point was length of recurrence-free survival.

Dr. Forget told Medscape Oncology that "the most important finding was the suggestion that intraoperative ketorolac given before surgery decreases relapse risk. The other analgesics have no detectable impact."

All patients had general anesthesia induced with sufentanil (0.0 to 0.2 μg/kg) and a hypnotic, sodium thiopental (4 mg/kg) or propofol (2 to 3 mg/kg). Anesthesia was maintained with a continuous infusion of propofol plus sevoflurane or desflurane in an oxygen/air mixture.

Intraoperative analgesia was chosen by the 2 anesthesiologists in charge: sufentanil (total dose, 0.0 to 0.5 μg/kg), preincisional clonidine (0 to 6 μg/kg), and preincisional ketamine (0.0 to 0.5 mg/kg), or preincisional ketorolac (20 mg intravenously in patients weighing <60 kg, 30 mg in patients weighing >60 kg).

Postoperative analgesia was intravenous piritramide titrated until visual analog scale scores were below 4. All patients received acetaminophen during the first 48 hours and oral diclofenac 50 mg twice daily for 3 days as necessary.

Importantly, no opioids were given during or after surgery.

Median follow-up was 27.3 months. After adjustment for age, histologic grade, and lymph node involvement, the researchers found that intraoperative administration of ketorolac was associated with a significantly lower risk for cancer recurrence (6% vs 17%; P = .019).

Sufentanil, clonidine, and ketamine had no significant effect on cancer recurrence rates.

The authors note that, "in contrast to previous data suggesting a negative influence of opioids on cancer-related immunity," in this study, sufentanil (given preoperatively) had no deleterious effect on cancer recurrence. "One reason may be the doses used in our patients, which are relatively small in comparison to those in other series. This is consistent with the fact that opioid-induced immunosuppression is dose dependent," they add.

Dr. Forget said that "intraoperative analgesics have a great influence on anticancer immunity. These effects must be evaluated before concluding the effect on the outcome. Such studies add a rationale for the use of nonsteroidal anti-inflammatory drugs [NSAIDs] in cancer patients [experiencing pain], but must be confirmed."

Oncologists must have an interest in the possible long-term impact of intraoperative analgesics.

"These data are not definitive evidence, mostly because of the retrospective nonrandomized design of the study," Dr. Forget continued. "But the change is that prospective studies are now clearly needed. Anesthesiologists, surgeons, and oncologists must have an interest in the possible long-term impact of intraoperative analgesics."

This conclusion was strengthened by a review article by Antje Gottschalk, MD, and colleagues published in the same issue of Anesthesia & Analgesia, which examined the role of the perioperative period in recurrence after cancer surgery. Dr. Gottschalk is from the Department of Anesthesia at the University of Virginia in Charlottesville.

The authors of the review note that surgery creates "profound metabolic, neuroendocrine, inflammatory, and immunological stress," increasing mediators that can upregulate major promalignant pathways and disrupt normal tumor homeostasis.

After reviewing clinical and preclinical data on the possible effects of type of anesthesia on that process, Gottschalk et al conclude that "beneficial approaches might include a selection of induction drugs such as propofol, minimizing the use of volatile anesthetics and the coadministration of cyclooxygenase antagonists with systemic opioids." They and Dr. Forget suggest more use of regional anesthesia.

When NSAID Administered Is Important

Interestingly, Dr. Forget's data suggest that when the NSAID is given matters as much as whether it is given. Breast cancer recurrence was lower in patients given preincisional ketorolac but not in those who received postoperative diclofenac.

Dr. Bovill notes in his editorial that surgery inhibits natural killer (NK) cells, the only cells able to recognize and lyse cells lacking self HLA-1 molecules. NK cells are the first line of defense against primary tumors and the metastatic spread of established tumors.

Inhaled anesthetics reduce NK activity, he points out.

Regarding the Forget study, Dr. Bovill writes that despite the fact that it was a retrospective nonrandom study in which patients received a number of other drugs, "the analysis of their data is sufficiently robust that the implications of their findings cannot be ignored."

Dr. Forget cautioned that "the possibility that perioperative management may alter the rate or incidence of recurrence is tremendously exciting, but much more research is needed for this possibility to be conclusively demonstrated."

The authors have disclosed no relevant financial relationships.

Anesth Analg. 2010;110,1524-1526, 1630-1635, 1636-1643. Abstract, Abstract, Abstract

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