Effects of Anesthetics on Cancer Recurrence
Jonathan Moss Department of Anesthesia and Critical Care, The University of Chicago, Chicago, IL
Robert J. Israel
Medical Affairs, Progenics Pharmaceuticals, Tarrytown, NY
To the Editor:
We read with great interest the recent article by Weckermann
et al
1 on the perioperative activation of disseminated tumor
cells in bone marrow of patients with prostate cancer. The authors
postulate "unknown perioperatively acting triggers that stimulate
outgrowth of DTCs" (disseminated tumor cells). Recent clinical
and laboratory data suggest that anesthetic technique may play
a role in tumor dissemination and recurrence. This issue has
been highlighted in the anesthesia literature in a recent article
of the
Anesthesia Patient Safety Foundation Newsletter, which
reviews the clinical and laboratory data for such an effect.
2 In a retrospective study of prostate cancer,
3 there was a significant
difference in the rate of tumor recurrence contingent on the
type of anesthesia used. A small retrospective study in breast
cancer had similar findings.
4 A large, multicenter, prospective,
randomized trial investigating the influence of type of anesthesia
on breast cancer recurrence is currently underway.
5
In addition to the clinical studies, there is also an evolving
basic science literature suggesting that opiates affect tumor
growth. Both we
6 and Gupta et al
7 have shown that clinically
relevant concentrations of opiates can cause endothelial cell
proliferation and migration in vitro. The proangiogenic effect
of mu opioid agonists seems to be the result of reciprocal transactivation
of the vascular endothelial growth factor receptor. We have
also demonstrated that mu opioids induce a defect in barrier
function, potentially allowing penetration of tumor cells.
8 The effects of mu agonists on both angiogenesis and barrier function are reversed by tertiary opiate antagonists or by methylnaltrexone, a peripherally acting mu opioid receptor antagonist approved in the United States to treat opioid-induced constipation in patients with advanced illness receiving palliative care when response to laxatives has not been sufficient.9,10
If these laboratory studies are confirmed clinically, then the
selection of anesthetic technique used during the operative
procedure and the possible use of peripheral mu opioid receptor
antagonists in the perioperative period may be of potential
importance. It would be particularly interesting if the authors
were able to review the perioperative records of their patients
to see which drugs were administered and what anesthetic techniques
were used.
We commend the authors for their diligent work and believe that
their observations deserve additional investigation.
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership Position: Robert J. Israel, Progenics
Pharmaceuticals (C) Consultant or Advisory Role: Jonathan Moss,
Progenics Pharmaceuticals (C) Stock Ownership: Jonathan Moss,
Progenics Pharmaceuticals; Robert J. Israel, Progenics Pharmaceuticals
Honoraria: Jonathan Moss, Progenics Pharmaceuticals Research
Funding: None Expert Testimony: None Other Remuneration: Jonathan
Moss, patent holder, methylnaltrexone
REFERENCES
1. Weckermann D, Polzer B, Ragg T, et al: Perioperative activation of disseminated tumor cells in bone marrow of patients with prostate cancer. J Clin Oncol 27:1549–1556, 2009.
[Abstract/Free Full Text]
2. Durieux ME. Does anesthetic management affect cancer outcome?
http://www.apsf.org/assets/Documents/winter2009.pdf.
3. Biki B, Mascha E, Moriarty DC, et al: Anesthetic technique for radical prostatectomy surgery affects cancer recurrence: A retrospective analysis. Anesthesiology 109:180–187, 2008.
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4. Exadaktylos AK, Bugy DJ, Moriarty DC, et al: Can anesthetic technique for primary breast cancer surgery affect recurrence or metastasis? Anesthesiology 105:660–664, 2006.
[CrossRef][Medline]
5. Sessler DI, Ben-Eliyahu S, Mascha EJ, et al: Can regional analgesia reduce the risk of recurrence after breast cancer? Methodology of a multicenter randomized trial. Contemp Clin Trials 29:517–526, 2008.
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6. Gupta K, Kshirsagar S, Chang L, et al: Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth. Cancer Res 62:4491–4498, 2002.
[Abstract/Free Full Text]
7. Singleton PA, Lingen MW, Fekete MJ, et al: Methylnaltrexone inhibits opiate and VEGF-induced angiogenesis: Role of receptor transactivation. Microvasc Res 72:3–11, 2006.
[CrossRef][Medline]
8. Singleton PA, Moreno-Vinasco L, Sammani S, et al: Attenuation of vascular permeability by methylnaltrexone: Role of mOP-R and S1P3 transactivation. Am J Respir Cell Mol Biol 37:222–231, 2007.
[Abstract/Free Full Text]
9. Methylnaltrexone (Relistor) for opioid-induced constipation. Med Lett Drugs Ther 50:63–64, 2008.
[Medline] 10. Moss J, Rosow CE: Development of peripheral opioid antagonists: New insights into opioid effects. Mayo Clin Proc 83:1116–1130, 2008.
[Abstract/Free Full Text]
http://www.joacp.org/index.php?optio...&id=60&catid=1
| Anesthesia May Affect Metastasis Risk After Cancer Surgery |
Does the type of anesthesia administered to a woman during surgery to remove breast cancer affect the odds that her disease will return or spread? Does the type of anesthesia administered to a woman during surgery to remove breast cancer affect the odds that her disease will return or spread?
As tenuous as that link might first appear, a new study by U.S. and European researchers suggests just that: Women who undergo regional and general anesthesia during their tumor operations face one-quarter the risk for local or metastatic recurrence of women given only general anesthesia during the procedure and opioids afterwards.
The researchers stress that their study, reported in the journal Anesthesiology (2006;105:660-664), is retrospective and preliminary and must be confirmed in a prospective trial. However, the results echo animal studies that support the hypothesis that general anesthesia and opioid drugs to prevent post-surgery pain create an environment that, albeit short-lived, encourages the growth and spread of cancer cells.
Daniel Sessler, MD, Chair of Outcomes Research at the Cleveland Clinic in Ohio, and senior author of the study, was cautious about exaggerating the importance of his group’s findings. “Retrospective studies are highly suspect, and that’s why I’m not going around saying this is true,” Dr. Sessler said. “However, it is nice preliminary data that supports the need for a major outcome trial.” He and his colleagues are now organizing such a study, which will require “thousands” of patients at multiple sites.
Dr. Sessler and other experts believe the results—“strange as they might seem,” he added—are well rooted in experimental and anecdotal evidence. Studies conducted in animals and humans suggest that the type of anesthesia used during surgery, the operation itself and opioid analgesia all sap the immune system.
“What determines whether cancer surgery is successful is largely a function of host defense—that is, whether the patient’s immune system can deal with the little bit of tumor that’s left and kill it off,” Dr. Sessler said. “If we do things that impair immune function exactly at that time, it seems likely to diminish the chances of cleaning up the residual tumor.”
Stunned Defenses Give Tumor Cells A Second Chance
Breast cancer is the most common form of cancer among women and the second leading cause of cancer-related death, next to lung cancer, in the United States. The vast majority of women with the disease undergo surgery to remove their tumor or tumors, as well as part or all of the affected breast. But surgeons cannot cut away every trace of cancer, so small numbers of tumor cells remain in the operating site that eventually can seed either local or distant recurrences. These cells are called micrometastases or minimal residual disease (MRD).
Ideally, the body’s cellular and humeral immune system will detect and destroy residual disease before it can erupt. As a stopgap, though, women also frequently receive chemotherapy and radiation after tumor surgery.
At the heart of the new study is a connection, supported by a growing body of evidence, between anesthesia, opioid pain relief and the immune system’s response to cancer surgery.
“Cancer surgery as done normally is bad for the immune system because the surgery itself, the anesthesia itself and the opioids used to control pain all impair natural killer cell function,” Dr. Sessler said.
Although ranking the insults is difficult, surgery may deliver the single biggest blow to the immune system. The body responds to the stress of the procedure by impeding the performance of natural killer cells. It also suppresses chemicals that deprive tumors of their blood supply and boosts the production of molecules, including vascular endothelial growth factor (VEGF), that stimulate their growth.
Animal studies also have suggested that anesthesia weakens the activity of natural killer cells, which lead the attack against cancerous cells and pathogens. Compared to general anesthesia, regional techniques may allow more killer cells to proliferate, raising the chances that these cells will be able to catch any leftover cancer cells.
Similarly, morphine and other opioids have been shown to suppress the immune system and, in particular, natural killer cells. Regional anesthesia during surgery can reduce the need for postoperative opioids, which may in turn leave the immune system stronger.
Much of the research in this area has come from the laboratory of Shamgar Ben-Eliyahu, PhD, Professor of Physiology and Psychology at Tel Aviv University, in Israel. Over the past decade, Dr. Ben-Eliyahu, an expert in neuroimmunomodulation, has published a series of studies, many funded by the U.S. National Institutes of Health, illuminating the effects of surgery, anesthesia and analgesia on human and animal tissues.
In what he called a “crucial” article (Anesthesiology 2001;94:1066-1073), Dr. Ben-Eliyahu and colleagues showed that rats given a spinal blockade—which reduces the neuroendocrine stress response to surgery—in addition to general anesthesia developed 70% fewer lung metastases after laparotomy than animals that received general anesthesia alone.
Then, in a study published in Neuroimmunomodulation (2004;11:255-260), Dr. Ben-Eliyahu and fellow investigators demonstrated that the opioid fentanyl inhibited the activity of natural killer cells in rats inoculated with tumor cells and increased the rodents’ risk for metastatic cancer. The tumor burden rose with the dose of fentanyl the animals received.
Dr. Ben-Eliyahu said the newest research adds an important clinical piece to the puzzle he has been completing. Led by Aristomenis K. Exadaktylos, MD, an anesthesia research fellow at Mater Misericordiae University Hospital in Dublin, Ireland, the researchers compared rates of recurrence and metastasis in 129 women who had undergone breast cancer surgery at that institution between September 2001 and December 2002. Of those, 50 received paraverterbral anesthesia—consisting of a 0.2-mL/kg bolus of 0.25% levobupivicaine—before induction of general anesthesia. For the general regimen, anesthesia was induced with 0.5 mcg/kg of fentanyl and 1.5-3.0 mg/kg of propofol (Diprivan, AstraZeneca), after which the women were given a laryngeal mask airway through which was administered 2% to 3% sevoflurane in nitrous oxide and oxygen.
Every woman also was given a 100-mg suppository of diclofenac after induction but before surgery, along with 0.05-mg/kg boluses of morphine during the operation at the discretion of the anesthetist.
Over the next three years, three women (6%) who received paravertebral anesthesia developed recurrent or metastatic tumors, compared with 19 of the 79 (24%) who received general anesthesia alone. At 36 months after surgery, 94% of women in the first group remained free of disease, compared with 77% of the others (P=0.007). Paravertebral anesthesia also seemed to delay the return of breast cancer (P =0.013) in the women who went on to suffer recurrences.
The researchers found no statistically significant differences in tumor grade, disease progression, adjuvant treatment, age and other factors among women in the two study groups. However, they noted, women who received general anesthesia alone tended to have slightly larger tumors, smaller tumor margins and higher rates of receiving chemotherapy than the other women—which could have influenced the outcome of the study.
Study Method Faulted
Critics of the research pointed to its retrospective nature and the inability to control for factors that might have biased the results.
“It’s very unclear whether the groups of patients receiving the blockade were equivalent to the patients who didn’t,” said E. Andrew Ochroch, MD, Director of Thoracic Anesthesiology at the University of Pennsylvania Health System in Philadelphia and co-author of an editorial accompanying the Anesthesiology article. The study “seems to be pushing us in the direction that the blockade is very, very good, but I believe that’s a false assumption. There’s not enough data to show that.”
Still, Jonathan Moss, MD, Professor of Anesthesiology and Critical Care at the University of Chicago Hospitals, called Dr. Sessler’s study “intriguing” and said it could have far-reaching implications for the care of patients with cancer if confirmed. “What happens during the course of your hospital surgery and anesthesia can really affect your well-being two years out,” Dr. Moss said.
Support for a direct connection between analgesia and tumor growth has come from recent studies demonstrating that opioids in clinical doses potentiate endothelial cell migration and proliferation, two components of angiogenesis that improve gastrointestinal recovery from the effects of surgery. In an article recently published in the journal Microvascular Research, Dr. Moss and colleagues showed that methylnaltrexone, a peripheral opioid receptor antagonist being developed by Wyeth and Progenics for postoperative ileus and constipation from opioid use, blocks opiate- and VEGF-induced angiogenesis in human lung and skin cells. “An effect of opioids on tumor proliferation could also explain the findings in [Dr. Sessler’s] study,” Dr. Moss said. “In addition to the opiates we routinely give, endogenous opioids go up quite substantially during surgery, and maybe even into the postoperative period.”
To be sure, the new research raises a host of questions. One of them is the relative impact on immune function of anesthesia, analgesia and the physical act of surgery. Another, the optimal time frame for quashing MRD and minimizing the odds of recurrence. Although Dr. Ben-Eliyahu cannot be certain, he believes this window is extremely small. “I cannot tell you whether it is a week or a month—nobody can,” he said. “My gut feeling is that it’s a matter of days. All our animal studies show that it is a very short period of opportunity.”
Whatever the case, Dr. Moss predicted, the study is certain to trigger additional interest in the intersection between anesthesia, surgery, pain relief and cancer. “I think people are going to be scurrying around to look at the data.”
Vol. 11, No. 4, 2004
Free Abstract Article (References) Article (PDF 125 KB)
Original Paper
Effects of Fentanyl on Natural Killer Cell Activity and on Resistance to Tumor Metastasis in Rats
Dose and Timing Study
Yehuda Shavita, Shamgar Ben-Eliyahub, Alexander Zeidelc, Benzion Beilinc
aDepartment of Psychology, Hebrew University, Jerusalem,
bDepartment of Psychology, Neuroimmunology Research Unit, Tel Aviv University, Tel Aviv, and
cDepartment of Anesthesiology, Rabin Medical Center, Golda-Hasharon Campus, Petah Tiqva, Israel
Address of Corresponding Author
Neuroimmunomodulation 2004;11:255-260 (DOI: 10.1159/000078444)
 Key Words- Opiates
- Natural killer cells
- Lung tumor retention and metastasis
Abstract
Objectives: Opiates, which serve an integral role in anesthesia, suppress immune function, particularly natural killer cell cytotoxicity (NKCC). NK cells play an important role in tumor and metastasis surveillance. We reported that large-dose fentanyl anesthesia induced prolonged suppression of NKCC in patients undergoing abdominal surgery. The immune modulatory effects of opiates may depend on the interaction between dose and time of administration. The present study examined the effects of different doses of fentanyl, administered at different time points relative to tumor inoculation, on NKCC and on experimental tumor metastasis in rats. Methods: Fischer 344 rats were injected with low or high doses of fentanyl, 6 or 2 h before, simultaneously with or 1 h after being inoculated intravenously with MADB106 tumor cells. Lung tumor retention (LTR) was assessed 4 h after, and lung tumor metastases were counted 3 weeks after tumor inoculation. NKCC was assessed 1 h after the fentanyl injection. Results: At all time points, except 6 h before tumor inoculation, fentanyl (0.1-0.3 mg/kg) induced a dose-dependent increase in MADB106 LTR (2.3- to 74-fold). An intermediate dose of fentanyl (0.15 mg/kg) doubled the number of lung metastasis, and, within animal, suppressed NKCC and increased MADB106 LTR in a correlated manner. Conclusion: These findings indicate that fentanyl suppresses NKCC and increases the risk of tumor metastasis. Suppression of NK cells at a time when surgery may induce tumor dissemination can prove to be critical to the spread of metastases. It is suggested that the acute administration of a moderate dose of opiates during surgery should be applied cautiously, particularly in cancer patients.
Copyright © 2004 S. Karger AG, Basel
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