Metronomic chemotherapy haemangiosarcoma

RE: Metronomic chemotherapy haemangiosarcoma

Sarah Keir — Fri, 28 Aug 2020 14:19:46 GMT

Former Member I brought up the H&S issues with the clinic I'm locuming in and the boss is considering paying me to update their chemotheraputics H&S! In the past I have prepared practice policies and SOPs for the safe use of cytotoxics in the practice where I have worked. Am I biting off more than I can chew if I take this on? It is a small GP companion animal practice. I would dearly love to cut down their use of enrofloxacin too!

RE: Metronomic chemotherapy haemangiosarcoma

Sarah Keir — Sun, 23 Aug 2020 12:44:01 GMT

I've found these sources of info:

https://chemopet.co.uk/wp-content/uploads/Guidelines-ECVIM-Hazards-Cytotoxic-drugs-2nd-version-July-2007.pdf

https://vetgirlontherun.com/how-to-safely-give-chemotherapy-in-veterinary-medicine-vetgirl-veterinary-continuing-education-blog/#:~:text=3.,the%20escape%20of%20hazardous%20drugs. Is USA but still holds true for UK.

RE: Metronomic chemotherapy haemangiosarcoma

Sarah Keir — Sat, 22 Aug 2020 08:56:22 GMT

Beats From my understanding, PPE that has not contacted the cytotoxic substance can go into normal waste and not cytotoxic waste. Indeed, in previous practices the gown has been put in a bag and reused the next time if confident that no spillage or splash - which there shouldn't be with a closed system but that was not used in this case. This is by far not the only H&S concern I have in this practice!

RE: Metronomic chemotherapy haemangiosarcoma

Beats — Fri, 21 Aug 2020 22:10:55 GMT

Sarah Keir

I feel a separate tangent thread coming...

I've never administered doxorubicin as I have always considered it too dangerous to use for me. I have never been entirely clear, however, on in what way it is too dangerous (compared to say vincristine, LA immobilon, Somulose, chloramphenicol, tacrolimus, detomidine, cylap vaccine, cyclavance, a cyclophosphamide tablet, the oil immersion for the microscope, the bleach to clean the toilet etc etc).

I dislike the lumping together of all injectable "cytotoxic" drugs. Partly because I dislike the term "cytotoxic" (preferring "hazardous"), and partly because I dislike the lumping together of lots of different drugs with different (I presume) levels of risk to staff. Finally, when we talk about "injectable cytotoxic drugs" I read this to mean "vincristine and doxorubicin" as (other than on 1 or 2 occasions, and perhaps carboplatin on one occasion - not even sure it that's still a done thing for osteosarcoma) these are the only injectable drugs I have seen used in my career thus far (invariably for lymphoma) and I think it would be easier just to talk about the specific risks relating to the administration of these specific drugs - purely because that's all I've ever seen used in practice.

Then there is the term "anti-neoplastics", which again is a class of drugs based on therapeutic use and doesn't really help me generalise any rules for specific drugs used for this purpose (for instance, I can't imagine that L-asparaginase is in the top 10 riskiest things I've injected an animal with). Meloxicam may even be considered an anti-neoplastic in some instances I believe.

Then there is the issue that most "guidance" (that I can find online anyway) is for healthcare professionals in a human healthcare setting where their entire job may consist of administering injectable hazardous drugs (and then cleaning up after than patients they administered them to, including excreta etc).

The NIOSH (American) makes reasonable sense from this perspective, and I think an important concept in risk management that may on occasions be missed is frequency. If your boss is doing this for one lymphoma case every 2 years, then it may be that the same level of controls as a medical oncology nurse doing this 6 times a day are not necessary.

"The actual risk to healthcare workers depends on toxicity of the drugs, how the drugs can enter the body (e.g., dermal, inhalation, or ingestion), and how the drugs are handled—how they are manipulated, how often they are handled, and the exposure controls in place, such as the type of engineering controls and personal protective equipment (PPE) (see Table 5). For example, Dispensing a single tablet to a patient may pose a relatively low risk to the healthcare worker. A single pair of gloves may be adequate. Repeatedly counting, cutting, or crushing tablets may pose a higher risk for worker exposure than dispensing a single tablet and contamination to the workplace if exposure controls are not in place. If a containment device such as a BSC (Class II biological safety cabinet) or CACI (compounding aseptic containment isolator) is not available, then double gloves, a protective gown, respiratory protection, and a disposable pad to protect the work surface should be used. Preparing several intravenous doses of an antineoplastic drug typically poses a higher potential risk to the worker. In addition to double gloving and a protective gown, an engineering control such as a BSC or CACI, possibly supplemented with a CSTD (closed system drugtransfer device), is necessary to protect the drug, environment, and healthcare worker."

Nurses in healthcare settings appear to get reasonable exposure to these drugs (not sure whether this comes from administration primarily or the nursing afterwards of the patient with drug inside). Your boss / co-workers may get substantially less exposure from very sporadic use in the absence of controls as stringent as the nurses use.

Sucking out vincristine from a vial and injecting intravenously to a dog on an occasional basis does not, to me, seem a hugely risky procedure (but I may be totally wrong!). Where I am unclear is what additional risk is incurred by sucking out doxorubicin (larger volume) from a vial and injecting into a drip bag and then running into a patient? I think my boss does this (very sporadically) and sedates the patient for this when doing to reduce the risk of patient-induced accidents; I have always been, and remain, reluctant to have any involvement with administering doxorubicin to dogs, though I am not sure that I can objectively fault what she does as excessively risky?

Finally, I've never understood when I've been in a clinic and having donned a used surgical gown and injected vincristine into a patients iv extension set successfully (or, in my youth, simply off-the-needle...), why the gown often seems to end up in the "cytotoxic waste" bag? Surely this is only if one suspects it might have been contaminated which I would expect to be pretty much never? On a logical footing, it makes little sense to me that this is incinerated at 700degrees while my hair and goggles do not require such extreme treatment? Can I confirm that there is no need to bin PPE (i.e. a used surgical gown) into a "cytotoxic waste" stream purely because it was present when a drug was administered if it did not come into contact with the drug (in contrast to the iv cannula, extension set and anything used to touch this) and it will go happily into a normal yellow bag for incineration?

Some links:

https://www.hse.gov.uk/healthservices/safe-use-cytotoxic-drugs.htm

https://www.cdc.gov/niosh/docs/2016-161/pdfs/2016-161.pdf?id=10.26616/NIOSHPUB2016161

https://www.medicines.org.uk/emc/product/6112/smpc [SmPC for Doxorubicin]

Extract: "3. Personnel handling doxorubicin should wear protective clothing: goggles, gowns, disposable gloves and masks." [this doesn't specifically state a full length gown, but I guess that does seem common sense in preference to a kennel apron, and doesn't specify nitrile rather than latex gloves, but again this may be common sense and assumed? I'm guessing that your boss ironically probably will be wearing a mask for this now whether did or not before... but perhaps this is not the correct type of mask so far as the doxorubicin instructions go...]

Here is an extract from the Aludex SPC for comparison re the risks of bathing a dog:

"Prepare and use the dilution of the product in a well-ventilated area. Wear waterproof gloves, apron and face shield when handling the product."

RE: Metronomic chemotherapy haemangiosarcoma

Sarah Keir — Fri, 21 Aug 2020 20:04:12 GMT

Former Member Before I raise this with the practice, I want to check that this is a legal requirement not something aspired to. Do you have links to any legal stuff I can present to the practice boss?

RE: Metronomic chemotherapy haemangiosarcoma

Ex Member — Fri, 21 Aug 2020 11:36:15 GMT

Dear Sarah, I am afraid you said everything! As indicated by specific health and safety law in the handling of hazardous medications, injectable cytotoxic medications should be drawn wearing appropriate PPE (in the case of injectable includes googles, FFP2 mask, gloves covering long sleeved gown, in a area of low traffic that then is thoroughly cleaned. If a cytotoxic cabinet is not available then at least a closed system should be used for preparation and administration of cytotoxic medications, or doses should be pre-ordered from online pharmacies such as Chemopet but still PPE needs to be wore during handling and administration. And yes, everybody is responsible for health and safety in the practice, even if you are not the person handling the hazardous substance. you of course want to avoid confrontations, but there are polite ways to raise your concerns with the practice manager that should be happy to hear about it before receiving complaints should something go wrong. Regards, Chiara

RE: Metronomic chemotherapy haemangiosarcoma

Sarah Keir — Thu, 20 Aug 2020 17:13:36 GMT

Can I chip in with a question on safety of using chemo in practice, in particular doxirubicin. I'm a locum and found a vet drawing up doxirubicin in the prep room from what looked like a 100ml glass bottle, wearing latex gloves, a plastic apron (front only, no sleeves) and googles (like what would wear for dental extractions). I'm in a difficult situation as a locum but also I need to take partial responsibility for those around me especially young nurses!

RE: Metronomic chemotherapy haemangiosarcoma

Ex Member — Wed, 19 Aug 2020 22:13:37 GMT

Dear all, below is a useful link to prove that frusemide is needed to avoid the potentially very serious complication of sterile haemorrhagic cystitis as indicated by Gerry.

Also it is not personal experience or opinion or tradition to state that adjuvant chemo in the treatment of hemangiosarcoma is effective although I do agree long term results are still suboptimal; this does not equal to say that it is ineffective when chemo double up survival in general terms. From the many papers published on the topic and many with discordant or variable results, it is obvious not only that improvement in outcome is needed, but that adjuvant chemo works depending on stage, histo and chemo used so what is needed is definitely to learn more abiut this tumour to see what patients have higher chances to respond and find better protocols that may include immunotherapy and personalised medicine in the future. In the meantime It is and continues to be indeed evidence based to advise adjuvant chemo to patients with hemangiosarcoma and furosemide to patients on metromic chemo. Hope this clarifies it!

Regards and stay safe,

Chiara

Furosemide for prevention of cyclophosphamide-associated sterile haemorrhagic cystitis in dogs receiving metronomic low-dose oral cyclophosphamide

L Setyo¹, M Ma¹, T Bunn¹, K Wyatt¹, P Wang²

RE: Metronomic chemotherapy haemangiosarcoma

Roger Wilkinson — Sun, 15 Mar 2020 20:19:25 GMT

Just to chip in a bit more info, one more study below.

I always prefer chlorambucil for metronomic because of the cystitis issue...altho makes it significantly more expensive. As a non-oncologist my impression is that there's more published work with cyclophosphamide but nothing showing inferiority of chlorambucil (I may be wrong....). I'm probably tempting fate in saying that I've treated hundreds of dogs with metronomic chlorambucil and not knowingly seen a serious adverse effect yet.

When you say chemo definitely works Gerry; are you basing that on personal experience or on published work? Wendelburg et al. above quoted by Anthony tends to suggest that the stats had to be somewhat 'persuaded' that there was a benefit. Excuse me playing devil's advocate.

regards

Roger

Adjuvant anthracycline‐based vs metronomic chemotherapy vs no medical treatment for dogs with metastatic splenic hemangiosarcoma: A multi‐institutional retrospective study of the Italian Society of Veterinary Oncology
Laura Marconato Carmit Chalfon Riccardo Finotello Gerry Polton Maria E. Vasconi Maurizio Annoni Damiano Stefanello Paola Mesto Ombretta Capitani Chiara Agnoli … See all authors
First published:28 June 2019 doi.org/.../vco.12519
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Abstract
Treatment options for dogs with metastatic (stage III) splenic hemangiosarcoma are limited. A doxorubicin‐based chemotherapy regimen is commonly administered; however, there are no published data to support this practice. The aim of this study was to investigate the impact of maximum‐tolerated‐dose chemotherapy (MTD), metronomic chemotherapy (MC) and no adjuvant treatment on outcome in dogs with stage III splenic hemangiosarcoma undergoing splenectomy. Medical records of dogs with stage III splenic hemangiosarcoma that underwent splenectomy followed by MTD chemotherapy, MC or no adjuvant treatment were retrieved. Time to progression (TTP), survival time (ST) and toxicity were evaluated. One hundred three dogs were identified: 23 received adjuvant MTD, 38 MC and 42 were not medically treated. Overall median TTP and ST were 50 (95% confidence interval [CI], 39‐61) and 55 days (95% CI, 43‐66), respectively. Dogs treated with adjuvant MTD had a significantly longer TTP and ST compared with dogs receiving MC (median TTP, 134 vs 52 days, P = .025; median ST, 140 vs 58 days, P = .023, respectively). Dogs treated by splenectomy only had the shortest median TTP (28 days) and ST (40 days). However, treatment‐related adverse events (AEs) were significantly more frequent in the MTD group (P = .017). The outcome for dogs with metastatic splenic hemangiosarcoma is poor. While MTD showed greater efficacy compared to MC, toxicity was higher in this group. Treatment‐related AEs need to be carefully balanced against this modest survival prolongation when offering adjuvant MTD to dogs with advanced stage hemangiosarcoma.

RE: Metronomic chemotherapy haemangiosarcoma

Sarah Keir — Tue, 03 Mar 2020 18:11:30 GMT

My concern, is the studies that I have seen comparing chemo to no chemo in haemangiosarcoma, the survival of the non-chemo patients is much shorter than my personal experience over 18 years of how long these dogs live for.

RE: Metronomic chemotherapy haemangiosarcoma

Beats — Tue, 03 Mar 2020 13:57:37 GMT

Thanks Gerry Polton, helpful as always!

RE: Metronomic chemotherapy haemangiosarcoma

Gerry Polton — Tue, 03 Mar 2020 08:32:32 GMT

Chemotherapy definitely works in patients who have recovered from haemangiosarcoma surgery, whether it was bleeding at the time of presentation or not. In fact, it even works in cases that have metastasis though the value of extended life in those cases is a discussion that needs to be had.

I honestly don't recommend tranexamic acid though I am aware that many colleagues in oncology and critical care do. I'm not sure that truthful answer helps you very much.

Gerry

RE: Metronomic chemotherapy haemangiosarcoma

Beats — Mon, 02 Mar 2020 19:35:34 GMT

Gerry Polton, how convinced are you that chemotherapy is actually likely to significant increase life expectancy and/or quality of life in patients splenectomised with a bleeding haemagiosarcoma? I'm far from convinced and would value your insights and perspective both from studies and your own extensive experience.

Secondly, do you ever recommend tranexamic acid (or another anti-haemorrhage drug) as a maintenance therapy in such dogs, or a subset thereof?

RE: Metronomic chemotherapy haemangiosarcoma

Laura Dell'Abate — Mon, 02 Mar 2020 17:34:38 GMT

Thank you . The owners do not have a lot of money and I work in a first opinion practice where chemotherapy is not usually used. Doxorubicin is not an option unfortunately.
I was considering meloxicam and cyclophosphamide:)

Laura

RE: Metronomic chemotherapy haemangiosarcoma

Gerry Polton — Mon, 02 Mar 2020 16:28:28 GMT

Hope, not hops! Daydreaming again!

RE: Metronomic chemotherapy haemangiosarcoma

Gerry Polton — Mon, 02 Mar 2020 16:27:49 GMT

As a general comment about the use of metronomic cyclophosphamide, I would definitely use frusemide daily. 1mg/kg is enough. It reduces your risk of sterile haemorrhagic cystitis from about 30% to about 3%. Some patients will die from this complication if their cancer is not rapidly progressive. Perhaps this is less of an issue in canine haemangiosarcoma where prognosis is poorer. But I would urge you to treat in the hops of a better outcome and therefore you should, in my opinion, co-administer the frusemide.

Gerry

RE: Metronomic chemotherapy haemangiosarcoma

Anthony Dennison — Mon, 02 Mar 2020 16:15:10 GMT

I wouldn't use frusemide regularly, just ensure that the cyclophosphamide is given in the morning and the dog has plenty of access to water and able to go outside and urinate. metronomic chemo tends to be long term.

Are you using it alongside another drug, like doxorubicin? Not sure it will improve things:

Adjuvant Doxorubicin with or without Metronomic Cyclophosphamide for Canine Splenic Hemangiosarcoma

Arata Matsuyama, Valerie J. Poirier, Fernanda Mantovani, Robert A. Foster, and Anthony J. Mutsaers

https://doi.org/10.5326/JAAHA-MS-6540

This retrospective study investigated the outcome of 33 dogs with splenic hemangiosarcoma treated with surgery followed by adjuvant dose-intensified doxorubicin (DOX) with or without low-dose metronomic cyclophosphamide (LDM-C) maintenance therapy. Among the 33 dogs, 18 dogs received LDM-C. Clinical stage was available for all dogs (5 stage I, 18 stage II, and 10 stage III). Nine dogs had macroscopic, and 24 dogs had microscopic disease at the start of DOX treatment. Median progression-free survival (PFS) and overall survival were 125 and 133 days, respectively. Clinical stage and tumor burden (microscopic versus macroscopic) at the start of chemotherapy was prognostic for PFS. No significant difference was observed in PFS or overall survival for the addition of LDM-C after a completed DOX protocol (P = .563 and P = .148, respectively). Based on the results of this retrospective study, the addition of LDM-C therapy as a maintenance regimen following a completed protocol of DOX adjuvant treatment of canine hemangiosarcoma may not improve outcome.

However, this paper shows that using a combination of conventional chemo protocols and metronomic chemo is better than doing one or the other:

Survival time of dogs with splenic hemangiosarcoma treated by splenectomy with or without adjuvant chemotherapy: 208 cases (2001–2012)

Kristin M. Wendelburg, DVM; Lori Lyn Price, MAS; Kristine E. Burgess, DVM, MS; Jeremiah A. Lyons, MVB, PhD; Felicia H. Lew, DVM; John Berg, DVM

Department of Clinical Sciences, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA 01536. (Wendelburg, Burgess, Lyons, Lew, Berg); Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, and Tufts Clinical and Translational Science Institute, Tufts University, Boston, MA 02111. (Price)

Dr. Wendelburg's present address is Animal Specialty Hospital of Florida, 10130 Market St, Naples, FL 34112.

The authors thank Laurel Bifano, Grace Barnett, Keriann Cabral, Melissa DiFrancesco, Jessie Hamilton, and Stephanie Kozol for assistance in data collection.

Address correspondence to Dr. Wendelburg (kmw6624@hotmail.com).

Objective—To determine survival time for dogs with splenic hemangiosarcoma treated with splenectomy alone, identify potential prognostic factors, and evaluate the efficacy of adjuvant chemotherapy.

Design—Retrospective case series.

Animals—208 dogs.

Procedures—Medical records were reviewed, long-term follow-up information was obtained, and survival data were analyzed statistically.

Results—154 dogs were treated with surgery alone, and 54 were treated with surgery and chemotherapy. Twenty-eight dogs received conventional chemotherapy, 13 received cyclophosphamide-based metronomic chemotherapy, and 13 received both conventional and metronomic chemotherapy. Median survival time of dogs treated with splenectomy alone was 1.6 months. Clinical stage was the only prognostic factor significantly associated with survival time. When the entire follow-up period was considered, there was no significant difference in survival time between dogs treated with surgery alone and dogs treated with surgery and chemotherapy. However, during the first 4 months of follow-up, after adjusting for the effects of clinical stage, survival time was significantly prolonged among dogs receiving any type of chemotherapy (hazard ratio, 0.6) and among dogs receiving both conventional and metronomic chemotherapy (hazard ratio, 0.4).

Conclusions and Clinical Relevance—Clinical stage was strongly associated with prognosis for dogs with splenic hemangiosarcoma. Chemotherapy was effective in prolonging survival time during the early portion of the follow-up period. Combinations of doxorubicin-based conventional protocols and cyclophosphamide-based metronomic protocols appeared to be more effective than either type of chemotherapy alone, but prolongations in survival time resulting from current protocols were modest.