Breast cancer surgery appears to trigger accelerated growth of any remaining tumor cells, both in the breast and in more distant locations in the body. Morphine can also increase proliferation and migration of breast cancer cells, as well as promoting angiogenesis. In addition, morphine suppresses the immune system. Animal and human studies comparing surgery with and without morphine or other opiates have demonstrated that use of opiates increases the likelihood of breast cancer recurrence. On the other hand, use of the nonsteroidal anti-inflammatory drug (NSAID) Toradol (ketorolac) during surgery instead of morphine dramatically reduces breast cancer recurrence, according to one study.
Surgery stimulates metastasis
Surgery is the primary and most effective treatment of breast cancer. However, the stress response induced by surgery impairs immune system functioning, promotes postoperative infections, and increases inflammation. In fact, surgery appears to promote metastasis through its effects on both the remaining breast tissue and distant tumor cells that had already been disseminated to other parts of the body prior to surgery.
Changes at the site of the surgical wound have been reported to accelerate the growth of cancer cells and are suspected of increasing their metastatic potential. In other words, surgery that leaves some of the tumor cells behind might promote the proliferation and motility of these cells, thereby allowing their escape into circulation. While there may already be dormant cancer cells in distant sites (which might have been seeded years earlier) that could potentially develop into tumors, cancer cells made suddenly mobile as a result of surgery would result in new waves of micrometastases with at least equal probability of developing into new tumors.
Surgery has been shown to induce modifications in the expression of genes implicated in metastasis, leading to changes that accelerate metastatic tumor growth in remaining tumor cells. In one study, mice prone to lung metastases were implanted with mammary tumors that were allowed to grow for 21 days. The mice were then divided into two groups, one of which had their mammary tumors completely surgically removed. At the end of the study, the lung metastases of the two groups of mice were compared. Surgical tumor removal was associated with increased number and size of metastases. Further analysis demonstrated that primary tumor removal led to increased expression of genes involved in tumor cell adhesion, invasion, and angiogenesis. Another mouse study reported that surgical removal of mammary tumors generated patterns of metastatic dissemination significantly different from those observed in tumors not treated by surgery.
Evidence for morphine's influence on cancer relapse
Morphine appears to amplify the deleterious effects of surgery. Morphine has been found to increase proliferation, inhibit the immune response, and promote angiogenesis of breast cancer cells in the laboratory. Comparisons of breast cancer surgery performed with or without morphine or other opiates have reported lower rates of breast cancer recurrence for surgery without opiates:
- A study of 327 Belgian breast cancer patients that compared various analgesics and anesthetics used in mastectomies performed by a single surgeon reported that use of Toradol (ketorolac) during surgery resulted in far superior disease-free survival during the first five years after surgery than other analgesics used in the study. Toradol, an NSAID, is a non-selective (COX-1 and COX-2) COX inhibitor. The early relapse peak normally seen in breast cancer patients was all but absent: 92% of the Toradol group were relapse-free at the two year mark, compared to 78% of the non-Toradol group (who were given opiates). Toradol was the only anti-inflammatory drug among the pain killers studied, suggesting that suppression of the temporary systemic inflammation resulting from surgery could explain its effect.
- Another study was designed to investigate the properties of serum from breast cancer surgery patients who received different anesthetic techniques. The study was conducted by dividing 22 patients into two groups — one group received propofol for sedation plus a paravertebral block (spinal block) for pain; the second group received sevoflurane general anesthesia plus opiate pain medication. Blood was drawn from the patients after surgery and MDA-MB-231 triple negative breast cancer cells were treated with serum from both patient groups. The effects of the serum on cancer cell proliferation and migration were measured. Proliferation of breast cancer cells treated with serum from the spinal block group was significantly lower than that of cells treated with serum from the opiate group.
- An Irish study of mastectomy patients compared the outcomes of 50 women who had paravertebral anesthesia and analgesia compared to 79 who had general anesthesia plus postoperative morphine. After two years, 94% of the paravertebral patient group were free of breast cancer relapse compared to 82% of the general anesthesia plus morphine patients. After three years, the comparable figures were 94% and 77%.
- A study using a mouse model of breast cancer reported that while morphine does not appear to play a role in initiating breast cancer, it promotes the growth of existing tumors. Mice given morphine early did not develop tumors sooner or in larger numbers than control mice who received no morphine. However, when morphine was given after tumors had started to appear in the mice, it significantly promoted tumor progression and reduced mouse survival times.
Use of regional instead of general anesthesia is known to reduce the surgical stress response. However, the first study above did not use this approach — it was the use of Toradol instead of an opiate that appeared to account for the lower recurrence rate.
While larger studies must be completed and confirm the results concerning Toradol, there is enough evidence concerning morphine to warrant taking steps to avoid its use. Many lumpectomies could probably be performed under regional anesthetic without morphine. Breast cancer patients can request that Toradol or another NSAID be used during and after surgery and themselves avoid using morphine after surgery, as well as other opiates such as Vicodin, Oxycodone, and Percocet.
Common NSAIDs include aspirin, ibuprofen (Advil, Motrin), naproxen (Aleve), and Celebrex. Although study results concerning NSAIDs are inconsistent, previous studies have reported that aspirin and Celebrex both are associated with reduced breast cancer risk and recurrence, whereas Aleve might have less effect, and ibuprofen could actually increase risk. Over-the-counter NSAIDs should not be used before surgery because they increase risk of bleeding during surgery. Also, note that Celebrex has been shown to interfere with the effectiveness of Adriamycin (doxorubicin) and certain other chemotherapy drugs and should not be used during chemotherapy. Breast cancer patients should discuss this topic with their surgeons.
Below are links to recent studies on this topic. For a more complete list of studies, please click on morphine.