TORADOL (ketorolac) linked to Recurrence Prevention
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University of Iowa. "Combining NSAIDs With Chemotherapy, Radiation May Improve Cancer Treatment." ScienceDaily. ScienceDaily, 18 May 2007. .0
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So, as far as ketorolac and bleeding go, we have on the one hand, a 2014 meta-analysis the said perio-operative ketorolac doesn't increase bleeding, and at least with low-dose ketorolac, has fewer adverse events and better pain relief (http://www.ncbi.nlm.nih.gov/pubmed/24572864), and a 2015 meta-analysis that said perio-operative ketorolac doesn't increase bleeding (http://www.ncbi.nlm.nih.gov/pubmed/25647706). The first one sounded like they administered ketorolac post-operatively, but you can't really tell about the second one (I wish they'd use pre or post-op to make it clearer). And there was also this: "Is ketorolac safe to use in plastic surgery: a critical review" ( http://www.ncbi.nlm.nih.gov/pubmed/25825424), which reviewed six studies and found no association between ketorolac use and hematoma. Also, a 2001 study, "Incidence of hematoma associated with ketorolac following TRAM flap breast reconstruction," (http://www.ncbi.nlm.nih.gov/pubmed/11214049 ) which also found no association between ketorolac use and hematoma, but did note decreased use of narcotics by patients who used ketorolac.
On the other hand is the 2012 study Sassy posted, "Restrospective analysis of perioperative ketorolac and postoperative bleeding in reduction mammoplasty" ( http://www.ncbi.nlm.nih.gov/pubmed/22434401) that DID find a more than 3 fold increase in hematoma requiring evacution.
How much weight should that mammoplasty study have? It is the most directly relevant to breast surgery, but it doesn't seem supported by much else.
I'm wondering whether it's the perception that ketorolac causes more bleeding that has kept anyone in the U.S. from starting a clinical trial. Forget didn't mention bleeding as a factor to be weighed did he? If it was a significant risk, wouldn't that preclude the RCT he's doing? Couldn't a RCT be done with just lumpectomies, anyway? It seems like we could have at least had a retrospective study done in the U.S. by now...but no interest. Weird. Makes me curious what it takes to get sufficient interest to get a study going.
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Morning Falls, The "three fold increase" sounds ominus, but I thing looking at the actual number will give a better picture
Well that didn't work. Let me see what I can do
Event, n (%)
Control (n = 252)
Ketorolac (n = 127)
RR (95% CI)
Primary outcome
Hematoma evacuation
6 (2.4%)
11 (8.7%)
3.6 (1.4 to 9.6)
Secondary outcomes
Operative site bleeding
14 (5.6%)
21 (16.5%)
3.0 (1.6 to 5.7)
hematoma
23 (9.1%)
25 (19.7%)
2.2 (1.3 to 3.6)
> 2 dressing changes
10 (4.0%)
8 (6.3%)
1.6 (0.6 to 3.9)
Drains required
5 (2.0%)
2 (1.6%)
0.8 (0.2 to 4.0)
Transfusion required*
0
3 (2.4%)
N/A
Infection†
36 (14.3%)
23 (18.1%)
1.3 (0.8 to 2.0)
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Morning Falls, I was trying to bring the exact chart showing the comparison of the actual numbers from the RED. Mammo sudy. I'll have to work on it.
Sorry, I couldn't get it to transfer. I think if you have time to read the entire study and look at the numbers, it may influence what you feel about the words "three fold increase". The numbers were small, but when a % is applied hematoma's were greater in the Toradol group. I may have a different perspective from working in surgery. I look at these numbers and my first thought is no one died. May sound harsh, but that's a biggy. I've been in surgery when patients have bled out. The conditions were generally, related to trauma victims and other factors not cogent to this discussion. In this study very few needed a transfusion. In the body of the study, it was broken down to 1:16 chance of developing a hematoma. My mind can better deal with the presentation of 1:16 versus 'three fold increase'.
If someone were having a surgery and considering that a single drug given one time, can influence the stimulation of the growth of micro tumor cells either in the wound bed, circulating, or at a distant point The key is weighing the risk versus the benefit. I think this is the endpoint which someone needs to consider which is more important. i.e. recurrence prevention or hematoma prevention.
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Reduction Mammoplasty study: The total number in the Toradol group was 127. The total number in the control group was 252
This paragraph describes the numbers of hematomas developed in the Toradol(treatment) group as compared to the controls. There is a very nice chart in the study. I just couldn't get it to transfer.
Eleven patients (8.7%) in the treatment group and six patients (2.4%) in the control group required surgical hematoma evacuation (Table 4). Perioperative ketorolac administration was associated with a significantly greater relative risk (RR) of requiring surgical hematoma evacuation than the control group (RR = 3.6; 95% confidence interval [CI], 1.4 to 9.6). A number needed to harm of 16 was calculated for the primary outcome of requirement for surgical hematoma evacuation. The treatment group also experienced a significantly increased risk of hematoma formation not requiring surgical evacuation (RR = 2.2; 95% CI, 1.3 to 3.6). Three patients in the treatment group (2.4%) required a blood transfusion while no transfusions were required in the control patients (Yates correction = 3.37; P = 0.07).
I've brought the Reduction Mammoplasty link forward for ease of reference.
http://link.springer.com/article/10.1007/s12630-012-9682-z/fulltext.html
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I posted this below, then Falls and 123 brought studies re: the problems with autologous(self donated) blood to the discussion. I did not just delete this because it's an example of my mantra "Just when you think you know something look again". Autologous blood transfusion SHOULD NOT BE USED IN THE CANCER PATIENT
When approaching any surgery it is always appropriate to consider that bleeding may occur. Donating blood for your self is call an Autologous donation. The ideal is to start several weeks ahead. Have your doc write the order. That requires the office staff to make arrangements. There's a process. The office staff will find out if the insurance will cover the cost. I donated for myself for my hyster/ooph in 1996. I didn't for the BMX.
In doing this it is an extra trip to the donation area and time to donate. A few hours total.
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Falls the Tram Flap link didn't hyperlink the last two numbers. It doesn't bring up the right study. Here it is
http://www.ncbi.nlm.nih.gov/pubmed/11214049
I suggest C&P back to your post
Off to play awhile.
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Hi, Sassy thanks for finding the correct hyperlink for me. I copy and pasted a few times, but couldn't get it to go live (computers hate me). But at least it's the right one, now!
Thanks, also for the explanation of why you did not find the "greater than 3 fold" increase overly persuasive against using ketorolac.
Your mention of autologous blood donation brought to mind that I read there is an association with blood transfusions and greater risk of cancer recurrence (due to acute inflammatory burden in a immune depressed state, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC426031... ). I wonder if the effects would be less if the transfusion is your own blood?
Anyway, hope you are having fun!
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wow Falls a new breadcrumb. I'm having.computer problems ahh I can't search.Withdrawal lol.
Breadcrumb....Does Autologous blood initiate an inflammatory response? It would seem logical that it shouldn't' t b/c it is an absolute match. I can read and post from the Kindle. The link didn' work to me. Don't know if it's my kindle.
I'll post when lap top fixed. Loading problems with both kindle and lap top.
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well that's a no shit moment! That study probably shook up the blood banking world. Please, if you can see if they're is any follow up.
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Sure for which one?0
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Interesting comments:
Review Article:
J. P. Cata, H. Wang, V. Gottumukkala, J. Reuben, and D. I. Sessler
Editor's Choice: Inflammatory response, immunosuppression, and cancer recurrence after perioperative blood transfusions
Br. J. Anaesth. (2013) 110 (5): 690-701 doi:10.1093/bja/aet068
Abstract Full Text (HTML) Full Text (PDF)
Re:Inflammatory response, immunosuppression, and cancer recurrence after perioperative blood transfusion
Juan P. Cata, Anesthesiologist
The University of Texas - MD Anderson Cancer Center
Dear Editor, I have to thank Palomero-Rodriguez et al for their important contribution to this topic. Certainly, L-arginine and arginase I and II are important modulators of the immune response after blood transfusion. No less important is the evidence provided by several investigators suggesting that a deficiency of L-arginine also occurs as part of the stress response to surgery and this deficiency has been implicated as one of the mechanisms behind the known shift from a Th1 to a Th2 response after surgery.[1] This phenomenon may even been worsened by the transfusion of mainly "old" blood which would further deplete levels of L-arginine. Perhaps, a more relevant question to answer in the clinical setting is whether the administration of L-arginine in the context of perioperative immune-nutrition could ameliorate immunosuppression and perhaps improve long-term oncological outcomes in patients in whom blood transfusion cannot be avoided and undergo major surgery.[2]
1. Marik P and Flemmer M. The immune response to surgery and trauma: Implications for treatment. The journal of trauma and acute care surgery 2012; 4:801-08.
2. Marik P and Zaloga G. Immunonutrition in high-risk surgical patients: a systematic review and analysis of the literature. JPEN. Journal of parenteral and enteral nutrition 2010; 4:378-86.
Conflict of Interest:
None declared
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Published July 22, 2013
Inflammatory response, immunosuppression, and cancer recurrence after perioperative blood transfusion
Miguel A. Palomero-Rodriguez, Anesthesiology Department Laporta Baez Y, Sanchez-Conde MP, Mollinedo F
Salamanca University Hospital
Dear sir:
We read with interest the paper of Cata JP et al [1] concerning perioperative blood transfusions, inflammatory response and immunosuppresion. In this interesting review, the authors discuss the understanding of the mechanisms by which transfusion affects immune function and could affect cancer progression. The authors conclude that transfusion of allogenic blood causes substantial alterations to the anti- inflammatory/pro-inflammatory milieu in the recipient that seems to be proportional to the stored age of the blood products [2]. It seems that biological factors included in these packed red blood cell that affect the innate immune function, rather than leucocytes or solubles fractions, may be responsible for tumour promoting effects [1,2].
Arginase has gained importance due to the fact that NO synthases are dependent on the availability of L-arginine in the extracelullar enviroment. L-arginine is metabolized by NO synthase (NOS) to produce nitric oxide (NO) or by arginase to produce urea and ornithine, which is a precursor of polyamines, which are important during cellular proliferation. Expression of NO synthases and arginases could co-regulate each other. Depletion of L-arginine by macrophages has been postulated as one of the several mechanisms that causes a decrease in CD3-zeta chain expression in cancer. In a tumor microenviroment macrophages deplete arginine via their high arginase activity and profoundly downregulate the tummor infiltrating T cells. L-arginine deficiency caused by high arginase activity, both at the tumor site and in circulating blood has been associated not only with sustained tumor growth via polyamine synthesis but also with tumor escape from immune response. Although arginase has a short half-life of only a few hours in human blood, it might act in early stages of immunosuppression. High levels of free arginase following blood transfusion could underlie many of the deleterious outcomes, including immunosuppression and infection related processes associated with transfusion of bloodstored for long periods.
The proposed detrimental effects of prolonged blood storage have been attributed in part to haemolysis of packed erythrocytes stored for a prolonged period, which leads to an increased oxyhaemoglobin concentration and nitric oxide (NO) scavenging. Indeed, the haemoglobin level in the storage bag supernatant was found to be higher after 40 days of storage than after 3 days of storage, indicating increased haemolysis [3], and infusion of 40-day packed erythrocytes was recently suggested to lead to increased NO production from endothelial nitric oxide synthase (NOS), as a compensatory mechanism for reduced NO bioavailability caused by plasma oxyhaemoglobin scavenging of NO [3]. However, although leucoreduced units of packed red blood cells contain fewer than 5 x10-6 white blood cells, it should be noted that neutrophils, which undergo spontaneous cell death, constitutively express large amounts of arginase [4] and even small contamination of packed red cell bags by neutrophils might, therefore, produce significant levels of arginase activity, apart from that derived from the red cells themselves. Recently we found raised levels of free arginase in blood stored for long periods, which could corroborate these arguments and have implications for patients in whom immunosuppression is a major challenge [5].
Thus, we suggest that increased haemolysis might be an important aspect in blood transfusion, leading to elevated levels of arginase and NOS, and, thereby, to L-arginine depletion that could eventually affects immune function and cancer progression.
References
1. Cata JP, Wang H, Gottumukkala V, Reuben J and Sessler DI. Inflammatory response immunosuppression and cancer recurrence after perioperative blood transfusions. Br J Anaesth 2013; 110: 690-701
2. Atzil S, Arad M, Glasner A, et al. Blood transfusion promotes cancer progression: a critical role for aged erythrocytes. Anesthesiology 2008; 109: 989-97.
3. Berra L, Coppadoro A, Yu B, et al. Transfusion of stored autologous blood does not alter reactive hyperemia index in healthy volunteers. Anesthesiology 2012; 117: 56-63.
4. Munder M, Mollinedo F, Calafat J, et al. Arginase I is constitutively expressed in human granulocytes and participates in fungicidal activity. Blood 2005; 105: 2549-56.
5. Mollinedo F, Palomero-Rodriguez MA, Sanchez-Conde MP, Garcia-Navas R, Laporta-Baez Y, De Vicente Sanchez J, Suarez-Gonzalo L. Arginase as a new concern in blood transfusion. Blood Transfus. 2013 May 29:1-2.
Corresponding autor: Dr. Miguel Angel Palomero Rodriguez, Department of Anesthesiology, Salamanca University Hospital, Paseo de San Vicente s/n, E-37007, Salamanca, Spain E-mail: mapalomero@gmail.com
Dr. Faustino Mollinedo Instituto de Biologia Molecular y Celular del Cancer Centro de Investigacion del Cancer, CSIC-Universidad de Salamanca Campus Miguel de Unamuno, E-37007, Salamanca, Spain. E-mail: mapalomero@gmail.com
Conflict of Interest:
None declared
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Published July 19, 20130 -
remind me to go back and amend those autologous transfusion comments
EDIT: The studies on autologous(self donated blood indicate they're may be circulating tumor cells in the blood. Autologous blood may not be transfused back to the patient in the time that Toradol is still present doing it's magic. An Autologous transfusion then has the potential of reintroducing circulating tumor cells. NOT our goal.
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Thanks for the interesting articles, 123Justme! Sounds like both allogenic and autologous blood transfusions create an inflammatory response. Interesting that Cata raises the idea of L-arginine supplementation perioperatively to reduce immunosuppression. That seems like an easy and inexpensive fix!
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It sure does sound like that! I wonder what L-arginine is also used for. I'll have to look that up....0
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I'm back, but now out to a party See you tomorrow
LOve the energy here.0 -
Something was said here a few pages back, that I will echo...
When I got diagnosed, I knew nothing about breast cancer. Zero. But I am a researcher at heart. So I started using EVERYTHING at my disposal to gather all the information I could. Every relationship, every skill.
I had lots of questions. If there was a study I did not understand, I literally called up the researcher, getting contact info through google or with a little fancy footwork through various university operators etc. I actually made quite a few friends. The people researching seemed to really like knowing that someone other than academics were interested in what they were doing. There were several study treatment options I was considering, and through the various conversations I had I was able to make informed decisions. I was surprised how accessible and receptive almost all of them were.
So good stuff here ladies - keep asking those questions!!
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I've enjoyed following this discussion and following up the links as time allows and would like to thank each of you who are ferreting out studies and analyzing the results in detail. I really appreciate it.
I knew there was supposedly an increased risk for bleeding but opted to have Toradol perioperatively during my lx. and had no issues. I've used it for pain control following surgery and much prefer it to opiates both in terms of effectiveness and lack of annoying side effects.
I think it's interesting that surgeons will pooh pooh hematomas when patients present with them following procedures such as biopsy, etc., but will rely on quoting the supposed increased risk of hematomas when they don't want to use a drug such as Toradol. Frankly, I'd rather risk an hematoma than a recurrence. You'd think surgeons would prioritze that way, too.
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Hi Hopeful glad to see you here
I agree on the prioritizing. One of the things the studies don't talk about is dry surgical fields. That is the wound bed. Good capillary hemostasis is important to prevent a hematoma. In the one study on Reduction Mammo, it was discussed as to %% od hematomas in the control group. It was less than the Toradol group, but not worth not having Toradol.Falls and 123, The blood transfusion studies draw the same conclusion. The autologous blood is likely caring circulating cells. It will be interesting to see how this is resolved in the future.
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Morning Ladies
Dear brother had his kidney sx yesterday. Pathologist couldn't identify tumor. Isn't that interesting. Sent it off to Univ. of Mich. which is a NCCN center. Doing well. His Anesthiologist blew him off about Toradol. He even blew off it's use as a low level pain reliever that he doesn't worry about with sx. Blowing off both tells me he doesn't keep up with current reading or old reading. The use re: interfering with cancer recurrence is new 5 years old and not mainstream yet. The use as an adjunct to opiods during surgery goes back to 1994. But they're were no complications. Hoping this doesn't turn to shit. At brothers request, I emailed the exact question to ask re:Toradol use. Now if it ends up it was needed......
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Sassy - glad the surgery went ok but very sorry to hear the anesthesiologist was such a jerk about his request for Toradol. sometimes I think it's a control issue on their part, at expense of their patient's health and well-being.0
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Interesting. I didn't know anything about Toradol before my surgery but learned a lot about it aftetwards. Glad I got it. Seems like a crapshoot about who knows and who doesn't....
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Did a new thread. Add your favorite research sites.
https://community.breastcancer.org/forum/73/topic/834695?page=1#post_4485520
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123, it is a crapshoot. My brothers surgery is a case in point. I present them with current info.and a doc negates it. The family is nonmedical. Who do they believe and I'm not there to ask all the questions?
His tumor was found on a workup CT scan for heart valve surgery. They couldn't get a hold of me till 7days ago. Sunday, he asked for a list of questions to ask pre and postop. I emailed the info.
They research things out the wazho. I suggested they come here and read last week. He said to just write what he needed to know. He stated he was interested to hear what the docs would say. I stated that it was unknown for his surgery if Toradol could be used b/c( for retroperitoneal surgery) the risk of bleeding is different than what I researched here for BC. As it ended up, they didn't get him up last night as directed. As a consequence, he was started on a blood thinner this am. Heparin. Toradol would be contraindicated with an anticoagulant. But the preincision dose would have been worn off. I would have to look at the half-life to verify that, but it's a mute point now. He can't even be put on any NSAID.
Earlier in the spring when I found out he was looking forward to heart sx., I suggested he get his Cytochrome450 2D6, 2C9, 2C19, 3A4, 3A5, VKROC1 tested as the three italized are abnormal for me. He was frustrated angry at one point and stated " Why do you know about this and my doc hasn't mentioned any of it?"
BTW if you're interested in the Cytochrome info it was a soapbox item of mine in 2010 when Dh was having chemo issues. I had to do his drugs by hand with the help of Genelex. I was tested for the 3's when I found out they became available. If you look at the thread start with my posts in feb 2014.
https://community.breastcancer.org/forum/73/topic/798301?page=1
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Although not related to recurrence, migraine sufferers should consider avoiding Toradol, too. Immediately following my LX, I had some of the worst migraines of my life. I mentioned it the next time I saw my neurologist, she looked at my record to see the meds that had been used during surgery, and said they are known to trigger migraines. She said that if I ever had surgery again, I should request Toradol.
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Chicago, I think you meant to say that you would request for Toradol not to be used? I compliment your neurologist for doing the detective work to identify that Toradol was the source of your Migraines postop. That is 'due diligence" for sure. I like that doc
But you did have Toradol for your lumpectomy. If the connection is proven that Toradol as a single shot perioperatively i.e. preincision, could prevent your BC from reoccurring what would your choice be? Would you ask that it be used or not used?
Have you had a chance to read Forget's two studies? Her numbers are clean. By that I mean same surgeon, same anesthesiologists, same anesthesia approach. It would be great if all studies were this clean in data.
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