Dexamethasone---should it be avoided?

Fallleaves

I know a lot of you have more medical and scientific experience than I do, so I thought I would ask you for help trying to figure this out. It's kind of a puzzle.

Dexamethasone (Dex) is a steroid (or more specifically a corticosteroid, and even more specifically, a glucocorticoid, because it binds to glucocorticoid receptors that are on almost all animals cells). It is commonly used as an anti-inflammatory drug for many inflammatory illnesses (like rheumatoid arthritis) and some cancers like various leukemias, lymphomas and multiple myeloma. It is also used to treat swelling from brain tumors.

It is used with breast cancer, in several ways:

1) during surgery, to reduce postsurgical nausea and vomiting,

2) with chemotherapy, to reduce nausea and vomiting and hypersensitivity reactions, and

3) to reduce edema from brain metastases

I was curious what it's effects are during surgery. Surgery results in the release of a lot of proinflammatory cytokines that drive the growth of residual cancer, so I thought Dex might be beneficial as an anti-inflammatory. On the other hand, it could go too far and suppress the immune system so much that Natural Killer cells, which are our innate immune defense against cancer, would be hampered in killing the leftover cancer cells.

I looked for studies (which I have listed below) showing the effect of Dex used during surgery, on the length of disease free survival (DFS) and overall survival (OS). There were no studies that looked at the use of Dex with breast cancer surgery, but I did find ones on the perioperative use of Dex with endometrial cancer surgery (1) and ovarian cancer surgery (2), and there was no indication that it affected recurrence-free survival or overall survival. And in the endometrial cancer study there seemed to be a longer time to recurrence in those who had Dex (23 mo. vs. 18 mo.)

Another study that pointed to no detrimental impact of Dex, was a Danish study that found no increase risk in breast cancer among women who used glucocorticoids (3). However this was a study that included 13 different kinds of glucocorticoids, and did not look at use specifically related to surgery or chemotherapy, which are particularly sensitive times.

In the other column, there was a recent study that showed that use of Dex with rectal surgery lowered 3 year DFS from 71.8% to 62.3% (4), and a very small study that found no reduction in disease free or overall survival in colectomy patients who were given Dex, but DID find a statistically significant increase in distant metastasis (5).

Next I found four studies that indicated Dex inhibits the effectiveness of paclitaxel (Taxol). Two were studies of human breast cancer cell lines, and two were mouse studies using xenografts (human tissue transplanted onto mice) of human breast cancer (6, 7, 8, 9). Paclitaxel works by inducing apoptosis (inducing the cancer cells to self-destruct), and Dex upregulates anti-apoptotic pathways, in direct opposition to Paclitaxel. For those interested in the specifics, Dex opposes the upregulation of the NF Kappa B pathway by paclitaxel, and Dex upregulates the anti-apoptotic gene MKP-1, and downregulates the pro-apoptotic genes TRAIL, and Bid. There were mixed findings in these studies on whether paclitaxel increased cell proliferation, and in two other cell culture studies, one found that Dex reduced cell proliferation (10) and one found it increased cell proliferation (11). Both of those studies used the MCF-7 (estrogen receptor positive) line.

I couldn't find any studies showing the impact of Dex on the effectiveness of cisplatin in breast cancer treatment, however I did find two studies (12, 13) that showed Dex interfered in the effectiveness of cisplatin killing lung cancer cells. These were studies using cancer cells and xenografts on mice. One of the studies found Dex created resistance to lung cancer cell apoptosis in gemcitabine treatment, as well (13) There was one other study (from 1996) that was concerning (14). It involved the use of a different steroid drug, prednisone, with chemotherapeutic treatment with cyclophosphamide, methotrexate, and 5-fluorouracil. The use of prednisone allowed greater doses of the chemotherapy drugs, but did not improve disease free survival or overall survival. On the other hand, it doubled the risk of metastasis to the skeleton by the 13 year follow-up, and tripled the risk of second (non-BC) malignancies, and patients with larger tumors had triple the risk of metastasis to the skeleton.

There was nothing (I could find) about the use of Dex with edema caused by BC metastases. However there was a study looking at use of Dex with recurrent glioblastoma (15). That study found that use of greater than 4.1 mg of Dex a day had detrimental impact, reducing overall patient survival from 8.9 mo. to 6 mo. in those using chemotherapy. In those receiving a different kind of treatment, Dex. reduced OS from 11 mo. to 4.8 mo.

So, this all made me think we could probably use some clinical trials specifically looking at the impact of Dex use on breast cancer treatment! It also raised the question: are there alternatives to Dex in BC treatment? For surgically related nausea and vomiting, yes. Dexmedomidine, propofol, and many others. With chemo Dex is frequently administered with two other drugs to prevent nausea and vomiting, but Dex seems to be the ONLY drug used to prevent hypersensitivity reactions. I did find a study that found Dex could be used in the first two rounds of paclitaxel and then discontinued (16), which would minimize use. But nowhere did I find a regimen that totally eliminated Dex use. For brain metastases, there have been some studies that showed non-steroidal anti-inflammatories (NSAIDS), particularly COX-2 inhibitors, could be used (17). And another mouse study showed use of COX-2 inhibitors could block cancer cells from brain metastases from entering systemic circulation (18).

I think there should at least be a retrospective study (looking back through records) comparing patients who received Dex while having breast cancer surgery to those who didn't, to see if there was any difference in their recurrence rates and overall survival, AND to see if it increases risk of distant metastasis. And if there is a difference, then a randomized clinical trial looking at that. It would also be good to have a study comparing the standard treatment with Dex for chemotherapy patients, to one that minimizes use of Dex. There are other reasons to minimize Dex. Its side effects include hyperglycemia and increased risk of infection, among others. So a clinical trial could look at whether Dex impacts the effectiveness of treatment, and also the difference in side effects. With brain metastases, a trial could compare use of a COX-2 inhibitor with Dex for treatment of edema, to determine its effectiveness for that, and to see if it improves overall survival. And it would be good to compare impacts of Dex use on estrogen positive cancers and triple negative cancers and/or HER2+ cancers, because there may be some differences there.

I'd love to hear some input on this!

1) http://www.ncbi.nlm.nih.gov/pubmed/26583436

2)http://www.ncbi.nlm.nih.gov/pubmed/24299930

3)http://www.ncbi.nlm.nih.gov/pmc/articles/PMC349613...

4)http://www.ncbi.nlm.nih.gov/pubmed/25744813

5)http://www.ncbi.nlm.nih.gov/pubmed/24583820

6)http://www.ncbi.nlm.nih.gov/pubmed/14965221

7)http://www.ncbi.nlm.nih.gov/pubmed/16775428

8)http://www.ncbi.nlm.nih.gov/pubmed/16496381

9)http://www.ncbi.nlm.nih.gov/pubmed/26463651

10)http://www.ncbi.nlm.nih.gov/pmc/articles/PMC452604...

11)http://www.ncbi.nlm.nih.gov/pubmed/23693080

12)http://www.ncbi.nlm.nih.gov/pmc/articles/PMC236194...

13)http://www.ncbi.nlm.nih.gov/pmc/articles/PMC352566...

14)http://www.ncbi.nlm.nih.gov/pubmed/8740787/

15)http://www.ncbi.nlm.nih.gov/pmc/articles/PMC450639...

16)http://www.ncbi.nlm.nih.gov/pmc/articles/PMC341129...

17)http://www.ncbi.nlm.nih.gov/pmc/articles/PMC310963...

18)http://www.ncbi.nlm.nih.gov/pubmed/24614081

sas-schatzi

Falls, you should try to publish this. I ran across a place that you could submit it too, but can't remember where. Contact Kayb and see if she has a clue. You raise many interesting questions and your intergration of the material is solid. Try google keywords "Online publication and evidenced based research". Please put a sentence at the bottom of your topic box. "Common Law Copyright, can't be reproduced in whole or part without the authors permission". Nice job.

Fallleaves

Thanks, Sas, I appreciate your reading it!