Practical Considerations for the Management of Cancer-Associated Venous Thromboembolism: A Guide for the General Oncology Practitioner
Round 1
Reviewer 1 Report
In this review article, the authors succinctly review current best practices in the management of cancer associated thrombosis and lay out a pragmatic approach for oncologists treating such patients. Considering recent landmark trials in the field, as well as a limited number of articles directed towards Canadian physicians, this article is a timely and useful addition to the extant literature. Prior to acceptance, I recommend the following revisions.
Major revisions:
1. While overall, the authors provide practical guidance that expands on what is presented in guidelines, there are a few instances where this is not fully flushed out and the article would be strengthened by additional commentary both to aid the practicing oncologist in making treatment decisions and also to differentiate the article from already published reviews/ guidelines. Specifically, I recommend the following sections be addressed:
a. Page 9, 1st paragraph: As for unusual site thrombosis, the ASCO and ASH guideline both state there is inadequate evidence to make recommendations for the treatment of unusual site thrombosis and advise that factors such as diagnostic certainty, chronicity, extent of thrombosis and associated symptoms should be considered when deciding to start anticoagulation treatment[25,26].
While, I recognize that there is insufficient data to present blanket statements for unusual site thrombosis, the current section does little to help oncologists better understand and treat these types of blood clots. Suggest considering providing directionality for the factors (i.e. a chronic clot may favour observation over treatment etc.) and/ or general examples of where anticoagulation would or would not be indicated
b. Page 9, 2nd paragraph “ another oral anticoagulant was initially used or, if already on LMWH, increasing the dose of LMWH [25,26].”
Recommend including guidance/ parameters for how much LMWH should be increased (e.g. 20-25%)
c. Page 11, 2nd paragraph “Clinicians should be aware of the potential for drug-drug interactions that could lead to supra- or sub-therapeutic levels of DOAC and, when available, a pharmacist-led drug-drug interaction evaluation should be completed prior to starting a patient on anticoagulation or when there is a…”
Recommend including some examples of high risk drug interactions common to oncology.
d. Page 12, 1st paragraph “In these cases, the society guidelines suggest reviewing the product monograph of the anticoagulant to determine if it is safe to use in renal or liver dysfunction and if dose adjustments are needed[24–27].”
As with unusual site thrombosis, while ultimately decisions will not be made on a case-by-case basis, I recommend a brief overview of general parameters for anticoagulation in the context of renal/ liver dysfunction.
2. For instances in which recommendations are based on expert consensus opinion, recommend ensuring that the language reflects the lack of certainty in the evidence. Specifically this applies to:
a. Page 8, 2nd paragraph “ treatment with LMWH should be initiated and then a DOAC can be considered when the…
b. Page 11, 1st paragraph “bleeding risk such as gliomas or metastases from renal cell carcinoma or melanoma should receive LMWH given the shorter half-life compared to DOACs”
Recommend using similar language to that used in the original references (i.e. suggests considering)
3. Recommend including brief discussions on SSPE and impact of low weight/ cachexia as these are both very common in cancer patients and in my perspective, notable omissions.
Minor revisions:
4. Page 2, 1st paragraph “The objective of this paper will be to illustrate some of the important factors to consider when deciding” – suggest changing “will be” to “is”
5. Page 3, 2nd paragraph “and the high cost of these anticoagulants[16]” - Reference 16 does not address the cost of the anticoagulants. A separate reference should be used for this point. This should also be clarified as representing total cost, as in many instances due to coverage differences, patient costs for DOACs may be higher than LMWH
6. Page 3, 2nd paragraph “In comparison, the CARVAGGIO trial was the first major trial in which the study DOAC (apixaban) was not associated with an increased risk of major bleeding episodes compared to LMWH[19].” – CARAVAGGIO is misspelled. To keep consistency with previous sentence would write “In comparison, the CARAVAGGIO trial (apixaban) was the first major trial in which the studied DOAC was not associated with an increased risk of major bleeding episodes compared to LMWH[19].”
7. Page 3, 2nd paragraph – recommend a brief discussion of important methodological differences between the trials. Specifically as it relates to differences in patient population between the studies (i.e. differences in patients with brain metastases, GI and hematologic malignancies) for appropriate interpretation of results.
8. Page 3, 2nd paragraph “In the smaller ADAM-VTE trial, Apixaban…” – recommend lower case for apixaban
9. Page 4, 1st paragraph – missing period for last sentence
10. Page 8, 2nd paragraph – extensive PE, is not a universally defined term and I recommend removing
11. Page 8, 3rd paragraph “Other notable types VTE events” - Missing the word “of” before VTE
12. Page 9, 1st paragraph “the ASCO and ASH guideline both state” – guideline should be plural
13. Page 10, 1st paragraph “increased rates of GU CRNMB in patients receiving DOAC” – DOAC should be plural
14. Page 11, 1st paragraph “melanoma should receive LMWH given the shorter half-life compared to DOACs” - missing period at the end.
15. Page 11, 3rd paragraph – “However, there are limited real-world data” – replace “are” with “is”
16. Page 12, 2nd paragraph “In patients with high-risk features such as symptomatic segmental or more proximal PE, proximal deep vein thrombosis (DVT), or a history of or recurrent/progressive thrombosis, therapeutic doses of anticoagulation with platelet transfusion support to maintain platelet counts above 40–50..” – While this is addressed in part later on, I recommend specifically including that the above statement usually only applies for an acute thrombosis (e.g first 30 days). In addition, there is an extra word (bolded).
17. Page 12, 2nd paragraph “anticoagulation if platelet count falls below of 25 × 10…” – Extra word
Author Response
Please see the attachment
Author Response File: 
Author Response.docx
Reviewer 2 Report
This is a concise and well-written review that summarizes important factors to consider when deciding on anticoagulation therapy for a patient with cancer-associated thrombosis. The topic is timely and important. The authors should discuss the impact of age on anticoagulation therapy. Recent evidence show changes in the tissue microenvironments and vasculature, which can impact coagulation cite this PMID: 33536212 and other relevant articles.
Author Response
Please see the attachment
Author Response File: Author Response.docx
Round 2
Reviewer 2 Report
The authors have not addressed my comments in the revised manuscript.
Author Response
We did review this reference and although it is interesting, we felt it was out of the scope of this article as this article is intended as a practical guide for clinicians taking care of patients with cancer associated thrombosis, and not focused on pathogenesis
