Abstract
Venous thromboembolism (VTE) is a major complication in cancer patients despite anticoagulation. In fact this is the second cause of death in them, only behind the malignancy itself. Therefore, optimal treatment is crucial.
Low-molecular-weight heparin (LMWH) and direct oral anticoagulants (DOACs) have been included as therapeutic options based on clinical trials.
But the issue here is that there are other contributing factors to the VTE apart from the cancer, such as the anticancer treatment. In fact, the recent incorporation of CDK4/6 inhibitors, such as Palbociclib, has shown to increase these episodes.
We present a case of multiple recurrences of VTE despite anticoagulation, which only responded after a reduction in the dose of Palbociclib.
This should change clinicians’ perspective at the time of treating recurrent VTEs in this population and think promptly about a dose reduction of the anticancer treatment if known to be associated to VTE.
Background
Patients with cancer have an elevated risk of acute and recurrent venous thromboembolism (VTE) despite anticoagulation. This issue poses a challenge to clinicians as there is not good evidence to suggest the best practice in this situation1.
For many years, low-molecular weight heparin (LMWH) has been considered an optimal anticoagulant for cancer-related VTE, and more recent data have concluded that direct oral anticoagulants (DOACs) are also good alternatives2.
As such, in the event of recurrent VTE, the advice would include (based on retrospective studies) either escalating LMWH doses or switching from DOACs to LMWH3.
We present here a case of recurrent/new VTEs on a patient with metastatic breast cancer despite optimal anticoagulation, who only responded to a reduction of her antineoplastic treatment
Case Report
A 73 -year?old female with a background of breast invasive ductal carcinoma, oestrogen receptors (ER) positive and Her-2 negative, presented with a several weeks history of lateral chest pain on the left side.
She was otherwise healthy and quite active.
She underwent a MRI of her chest to check the status of her breast prosthesis. This showed an expansile lytic lesion in the anterior aspect of her left third rib suspicious of malignancy.
A CT scan confirmed this lesion and showed multiple bilateral pulmonary emboli and numerous small mixed sclerotic and lytic axial skeletal lesions. A bone scan was also performed and reported multiple small thoracic vertebral metastases and a few smaller lumbar deposits with a patchy uptake throughout the ribs and a left posterior skull metastasis.
The patient had not reported any shortness of breath, although, when asked retrospectively, she mentioned that perhaps recently she had noticed more difficulties when going for long walks or upstairs.
A therapeutic dose of LMWH was started and although initially a biopsy was planned, then this was abandoned due to risks considerations.
The patient was started on a combination of Letrozole and Palbociclib.
She coped well with this treatment but struggled with the daily LMWH injections and after 8 weeks of treatment, this was switched to Rivaroxaban after a discussion with the Haematologists.
A CT scan repeated 3 months later to assess response showed stable bone metastases but persisting multilobar pulmonary emboli. On further questioning, the patient reported more shortness of breath on the previous weeks. Rivaroxaban was then stopped and switched back to
LMWH therapeutic dose. Her shortness of breath improved significantly but she started to struggle again with the daily injections after 6 weeks on them.
This time she was switched to Apixaban 5mg twice daily and a later CT repeated 3 months after, reported an unchanged chronic thrombus in the proximal right lower lobe pulmonary artery and stable bone metastases.
Around 4 months later, the patient contacted us complaining of new shortness of breath on moderate exertion. Her CT was brought forward and it showed stable bone metastases but new pulmonary emboli in the segmental arteries and sub-segmental vessels in the left lower lobe.
Her treatment was switched again to LMWH monitoring anti-Xa. After an initial benefit, another CT showed again new pulmonary emboli without any clinical impact this time.
On further discussion with Haematology, the dose of LMWH was increased by 20% and we decided to reduce the dose of Palbociclib from 125mg to 100mg.
The patient had never had any signs of deep venous thrombosis and she had always been very active.
After around 4 weeks of daily injections, she could not cope anymore. It was then decided to try back Rivaroxaban.
Another CT was repeated after being >2 months again on Rivaroxaban. This CT did not show any evidence of new pulmonary emboli and continued to report stable disease.
Currently, >2 years later, the patient continues well, without any further changes and since the reduction on Palbociclib, her repeated CTs show no evidence of further VTE.
Discussion
Cancer associated thrombosis is a highly prevalent and potentially lethal complication in patients with malignancies. It has been estimated that the annual incidence of VTE in cancer patients is 0.5% in comparison to 0.1% in the general population4.
Moreover, VTE is the second most frequent cause of death from malignancy, second to cancer itself5.
It presents some peculiarities that differentiate it from other VTE such as different risk factors, pathological mechanisms, difficulties in diagnosis and uncertainties about optimal treatment.
Although breast cancers are associated with low risk of VTE in relation to other types of cancer6,
VTE is frequently detected anyway as breast cancer is one of the most prevalent neoplasias around the world.
Other risk factors contributing to VTE are the presence of metastatic disease, treatment with chemotherapy, mainly platinum or taxanes, tyrosine kinase inhibitors, immunomodulatory agents and more recently the cyclin dependent kinase (CDK) 4/6 inhibitors such as Palbociclib6,7.
Our patient presented here, had metastatic disease involving the bones and an incidental pulmonary emboli at diagnosis.
She was started on therapeutic dose of LMWH and palliative treatment with Palbociclib and Letrozole as first line for her metastatic breast cancer.
Although VTE events were rarely reported following this CDK4/6 inhibitor within PALOMA-1 (Letrozole vs Palbociclib and Letrozole) and PALOMA-3 (Palbociclib and Fulvestrant or placebo) clinical trials, overall an incidence of around 1.2-2% was confirmed8,9.
But this incidence seems to be low when compared to the real-world experience as reported by Watson et al. These authors confirmed an 11% incidence of VTE and they suggested that further research is needed to assess if a prophylactic anticoagulation should be considered for these patients10.
Typically patients present with symptoms of shortness of breath, chest pain, tachypnea or rapid heart rate and authors from those trials concluded that patients should be monitored for any of these symptoms.
Unfortunately, these symptoms, as in our patient, may be subtle and not considered relevant or the patient may not even present with any symptoms at all, at least for a period of time.
This makes even harder a proper diagnosis.
Our patient showed several episodes of VTE recurrence which unfortunately this is frequent despite being on anticoagulation, and this still poses a challenge to clinicians as there is not11,12
a high-quality evidence to guide practice in this situation.
For many years LMWH has been the standard as it had demonstrated superiority over warfarin in reducing the risk of VTE in patients with cancer13.
However, recently, the Hokusai VTE Cancer trial (Edoxaban for the Treatment of Cancer-Associated VTE)14randomised 1046 patients with cancer associated VTE to receive, after a minimum course of 5 days of LMWH, oral edoxaban or dalteparin 200 U/kg once daily for 1 month followed by 150 U/kg for at least 6 months and up to 12 months.
Edoxaban showed non inferiority in comparison to dalteparin and those patients also showed fewer episodes of VTE recurrence15.
The SELECT-D (Comparison of an oral factor Xa inhibitor with LMWH in patients with cancer with VTE) trial randomised 406 patients to receive rivaroxaban 15mg twice daily for 3 weeks followed by 20mg once daily for 6 months or dalteparin 200 U/kg once daily for 1 month followed by 150 U/kg once daily for 2–6 months16.
VTE recurrence rates were less frequent with rivaroxaban.
And the Caravaggio trial as well has shown non-inferiority of oral apixaban in comparison to dalteparin for the treatment of cancer-associated recurrent VTE17.
In fact, the International Society of Thrombosis and Haemostasis (ISTH) has suggested the use of rivaroxaban or edoxaban for cancer associated thrombosis in patients with low risk of bleeding, but to consider LMWH18as an acceptable alternative for cancer patients with a higher risk of bleeding such as gastrointestinal cancers.
The NCCN guidelines recommend LMWH as the preferred option in patients with a pulmonary embolism and advanced metastatic cancer, although rivaroxaban and apixaban are also accepted as alternatives, especially for patients who do not cope well with daily injections1.
Other recommendations have included changes between DOACs to LMWH or escalating LMWH doses by 20%-25% but these are based on limited retrospective studies2,19.
What strikes us is the fact that despite being anticoagulated following all the guidelines available, our patient continued presenting recurrent VTE until we finally decided to consider that as a Palbociclib induced adverse event of grade 3 and reduced the dose of this accordingly (following the guidance of common terminology criteria for adverse events version 5.0 published in November 2017).
Since then, she has continued on treatment, coping well without any further issues and maintained on rivaroxaban 20mg daily.
Her recent CT scan (>1 year after the reduction) continues stable and without any evidence of any new pulmonary emboli.
To our knowledge there is no other similar case published.
Learning points
- Patients with cancer are at a higher risk of recurrent VTEs despite appropriate anticoagulation with the subsequent risk of death.
- Oncologists should be fully aware of the role of the anticancer treatments as sources of VTEs in these patients.
- CDK4/6 inhibitors, such as Palbociclib, are a recent incorporation into the anticancer arsenal which might produce VTEs.
- In case of recurrent VTE in a correctly anticoagulated cancer patient, oncologists should think about this being an adverse event and try to manage it by reducing the dose of the anticancer treatment appropriately.
References
- Tzu-Fei Wang, Ang Li, David Garcia. Managing thrombosis in cancer patients. Res Pract Thromb Haemost. 2018;2:429–438. DOI: 10.1002/rth2.12102.
- Streiff M, Holmstrom B, Angelini D et al. NCCN Guidelines Insights Cancer-Associated Venous Thromboembolic Disease, Version 2.2018 Featured Updates to the NCCN Guidelines. Journal of the National Comprehensive Cancer Network, 2018:16(11)
- Ihaddadene R, Le Gal G, Delluc A, Carrier M. Dose escalation of low molecular weight heparin in patients with recurrent cancer-associated thrombosis. Thromb Res. 2014;134(1):93-5. doi: 10.1016/j.thromres.2014.04.028. Epub 2014 May 2.
- Elyamany G, Alzahrani AM, Bukhary E. Cancer-associated thrombosis: an overview. Clin Med Insights Oncol 2014; 8: 129–137.
- Khorana AA, Francis CW, Culakova E, et al. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost 2007; 5: 632–634.
- Gade IL, Braekkan SK, Naess IA, et al. The impact of initial cancer stage on the incidence of venous thromboembolism: the Scandinavian Thrombosis and Cancer (STAC) Cohort. J Thromb Haemost 2017; 15: 1567–1575.
- Venous thromboembolism in breast cancer patients receiving cyclin?dependent kinase inhibitors Lorenzo Gervaso1 | Alberto J. Montero1 | Xuefei Jia2 | Alok A. Khorana J Thromb Haemost. 2020;18:162–168.
- Turner NC, Ro J, Andre F, et al. Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med 2015; 373: 209–219.
- Verma S, Bartlett C, Schnell P, et al. Palbociclib in combination with fulvestrant in women with hormone receptor-positive /HER2- negative advanced metastatic breast cancer: detailed safety analysis from a multicenter, randomized, placebo controlled, phase III study (PALOMA-3). Oncologist 2016; 21: 1165–1175.
- Watson GA, Deac O, Aslam R, et al. Experience of Palbociclib-Induced Adverse Events and Compliance With Complete Blood Count Monitoring in Women With Hormone Receptor-Positive/HER2-Negative Metastatic Breast Cancer. Clin Breast Cancer. 2019;19(1):e186-e194. doi: 10.1016/j.clbc.2018.09.002.
- Francis CW, Kessler CM, Goldhaber SZ, et al. Treatment of venous thromboembolism in cancer patients with dalteparin for up to 12 months: the DALTECAN Study. J Thromb Haemost 2015;13:1028-35.
- Lee AY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003;349:146-53.
- Kearon, C, Akl, E.A, Ornelas, J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016;149:315–352.
- Raskob GE, van Es N, Verhamme P, et al. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018;378:615–624.
- Kraaijpoel N, Di Nisio M, Mulder FI, et al. Clinical impact of bleeding in cancer-associated venous thromboembolism: results from the Hokusai VTE Cancer Study. Thromb Haemost. 2018;118:1439–1449.
- Young AM, Marshall A, Thirlwall J, et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J Clin Oncol. 2018;36: 2017–2023.
- Agnelli G, Becattini C, Meyer G, et al. Apixaban for the Treatment of Venous Thromboembolism Associated with Cancer. N Engl J Med. 2020; 382:1599-1607
- Khorana AA, Noble S, Lee AYY, et al. Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: guidance from the SSC of the ISTH. J Thromb Haemost. 2018;16:1891–1894.
- Carrier M, Le Gal G, Cho R, Tierney S, Rodger M, Lee AY. Dose escalation of low molecular weight heparin to manage recurrent venous thromboembolic events despite systemic anticoagulation in cancer patients. J Thromb Haemost. 2009;7:760–5.
Acknowledgements
Many thanks to our patient for her collaboration with us in getting her case published. In fact, she would like to have her opinion seen.
"As this case shows, following a CT scan in later 2017 it was discovered that I had secondary breast cancer for which I was given Palbociclib 125 mg per day. The CT scan also found a pulmonary embolism.
I was immediately put onto Dalteparin. Not a great experience as too many injections. My tummy hurt. Several CT scans continued to show new embolisms and my anticoagulants were changed several times but none of them seemed work as expected.
This series of events led to a long time of worries and fears. I was feeling extremely vulnerable and it was finally suggested that I should have a decreased dosage of Palbociclib, 100 mg. I was initially reluctant but after yet another CT scan the embolism had gone and I was reviewed by my oncologist who changed my Dalteparin to Rivaroxaban. Since then I have had no further problems. I am happy to share my experience with others if this can help. "
Many thanks as well to Jayne Dalzell and to Kerry Hamer for their invaluable support and help.
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