Professor Andrés Muñoz a Medical Oncologist at Hospital General Universitario Gregorio Marañón, discusses the management of venous thromboembolism in women with cancer.

Watch selected highlights below

Gender and CAT

An overview of the insight taken from RIETE registry and RIETECAT cohort study.

Incidence of VTE in cancer patients

An overview of the GARFIELD registry and TESEO registry.

Thanks for the presentation. It’s a real pleasure and an honour to be a part of this meeting to talk about the management of venous thromboembolism in women with cancer: new insights from registries. I would like to thank to the organisers and to Sanofi team, to talk about a very interesting point that is cancer, women and thrombosis.

Some word about cancer in women in 2020, now we know that almost 19 million cancer cases were diagnosed around the world in 2020 with a lower incidence in women compared to men. But the most important thing is that female breast cancer has now surpassed the lung cancer as the leading cause of global cancer incidence in 2020, for the first time. So it’s quite important that breast cancer is the most common tumour in the world. Regarding females, we know that the most common tumours in females are, firstly breast cancer, colorectum, lung, cervix-uterine, thyroid and corpus uterine. We have to say that between the 6-7 most common tumours, three of them are called female cancers. And from a cancer point of view, I have to tell you we are doing the right things, we are on the right track, we are reducing the mortality due to cancer. These are data from the United States in the last 20 years, regarding different and most common female cancers but of course we are on the right track but we are far away from our point.

First data about gender and CAT (cancer-associate thrombosis). I have to tell you that gender female is a VTE (venous thromboembolism) risk factor, however in many studies in cancer patients have shown that no significant sex differences in VTE in cancer or maybe a lower importance of this risk factor. We have to say that gender in CAT is attenuated risk factor and it is less relevant compared to non-cancer patients. Regarding the different guidelines, we don’t have any specific recommendation by gender up to 2021.

We have to look to the RIETE registry published more than 5 years ago shows that in more than 11,000 patients we can have some differences based on gender of the patients, in the clinical characteristics. We know that women have less likely to have co-morbidities and more likely to present with severe PE (pulmonary embolism). In addition too, women receive higher low molecular weight heparin doses for initial and long-term therapy.

Regarding the main endpoints of this study from RIETE, more than 11,000 patients, we have to say that women, compared to men, had a significantly lower rate of fatal bleeding, and death and a non-significantly lower rate of PE recurrence and major bleeding, compared to men.

Also from RIETE, we had the data analysis for non-female cancer and they found very interesting data that women with VTE and lung, colorectal, pancreatic, heamatological and gastric cancer, considered the most common tumour regarding VTE risk, they experienced a similar rate of VTE recurrences, major bleeding or death, during the course of anticoagulant therapy, than men. So it seems that the differences are located in the typical female cancers.

And another important paper published by the RIETE group was one of the first paper that had a look at this very important issue: the site of cancer. They found that breast cancer could be considered a low risk cancer for recurrence and a low risk cancer for bleeding. So breast cancer seems to have a better prognosis regarding major bleeding or recurrence, compared to prostate, colorectal and lung cancer. So it could be interesting regarding strategy to perform anticoagulation in these patients.

The last study I want to review about the RIETE registry is the RIETECAT cohort study.

They analysed the big database of RIETECAT, how different low molecular weight heparins perform in the real world setting. RIETECAT was a multinational-observational retrospective cohort study using the RIETE registry containing patients who were 18 years old or more with active cancer, and acute episodes of symptomatic VTE, including proximal DVT (deep vein thrombosis) or PE (pulmonary embolism), in the period of time between 2009 and 2018 who were receiving treatment with full dose enoxaparin, tinzaparin or dalteparin. They analysed patients who received full doses and they defined full doses for enoxaparin 1 mg/kg every 12 hours or 1.5 mg/kg once a day. They compared this with traditional tinzaparin or dalteparin doses used in the randomised clinical trials. The main outcome of this study was to assess the VTE recurrence in a non-inferiority design.

If we have a look to the more than 4,000 patients that were included in this study, if we analyse the clinical characteristics, I have to highlight that the initial presentation of VTE, patients receiving enoxaparin had a higher incidence of PE with a significant P value and a higher use of anti-platelet therapy, again with a significant p value, compared to the other low molecular weight heparins that were analysed. Co-morbidities we could say don’t differ between the two groups and 92% of tumours were solid cancers. Again there were no differences in cancer site, except for breast cancer, that was less likely to be described in the enoxaparin group.

The main endpoint was positive, we didn’t observe any significant differences in the recurrence of VTE. Patients receiving enoxaparin had a numerically lower rate of VTE recurrence, 2%, than those on the tinzaparin or dalteparin, 2.5%, meeting the prespecified criterion for non-inferiority, with a significant p value. If we analyse major bleeding or non-major bleeding of clinical significance, we didn’t observe any significant differences in these two main outcomes of RIETECAT.

If we analyse the outcomes in 6 months, we analyse the mortality, we didn’t observe any significant mortality differences – 18.9% compared to 17.0%. And when we analysed the composite safety outcome we didn’t observe any significant differences between the two treatment arms. If we analyse the site of bleeding, the location of different bleeds was just the same with no significant differences and the fatal rate of bleeding was almost the same 0.43% with enoxaparin compared to 0.54% with the combination of the other drugs.

We can conclude from this study that extended treatment with full dose enoxaparin had a comparable effectiveness and safety profile to tinzaparin and dalteparin in cancer patients with VTE. To our knowledge we could say this is the largest study comparing effectiveness and safety of different low molecular weight heparins in the real world setting over 6 months with a long time period of anticoagulation. And we could conclude that enoxaparin is non-inferior in the two main endpoints of this study.

Just to conclude I would say that gender is a risk factor for VTE in cancer patients but the importance of gender as a risk factor for VTE is attenuated by other cancer variables such as stage of disease or type of tumour. And there are not specific recommendations in main clinical guidelines in 2021. Breast cancer is considered a low-risk cancer for VTE despite being a hormone-dependant cancer but a high-VTE prevalent tumour in the real life setting. Of course ovarian and uterus cancer are considered a high-risk tumour for VTE and for uterus cancer it is in the advanced stage of disease. Breast cancer should be considered a low risk tumour for recurrence and bleeding compared to other common cancers – colorectal, prostate or lung cancer. And finally from RIETECAT, it is one of the most important studies from this year in real-life clinical practice, extended treatment with full dose enoxaparin had a comparable effectiveness and safety profile to tinzaparin or dalteparin in cancer patients with VTE. Thanks very much for your attention and let’s go to the Q&A session.

Regarding the Garfield registry- another large international registry we observe similar data that again, in active cancer patients, women had a lower incidence of VTE compared to men – more men are included in this registry. And the very important data – the most common site of active cancer was lung, colorectal and in the third place, breast cancer. This is considered a low risk tumour for VTE. Breast cancer despite being a low risk tumour is a very prevalent tumour in our clinics of CAT.

If we analyse the different rates over 12 months in cancer patients, I have to tell you that we know that the recurrence rate is an important issue but we observe that the bleeding rate is at least as important as the recurrence rate. We have observed that bleeding has become a major issue nowadays and we really need a better knowledge of risk assessment models and we need a specific risk assessment model for bleeding because nowadays it’s an important issue for cancer patients. If we analyse the history of cancer with active cancer and no cancer we can say that history of cancer is just in the middle of cancer patients with active and non-active cancer. This is the message for the next studies that we don’t have to include history of cancer in the same analysis as active cancer. They have a different prognosis regarding recurrence rate and bleeding rate I think is in the middle between non-cancer patients and active cancer patients.

If we analyse again the 12 month different endpoints in the active cancer compared to the history of cancer and the most important, active cancer versus no cancer, we have observed a change in the last case of VTE and cancer and you can see the recurrence rate is lower in the last twenty years, we have learned to treat these patients. We are doing better things but still the bleeding is a major issue. The bleeding rate is higher than what was reported 20 years ago by Paolo [unknown]. Again, we need to better understand the risk factor for bleeding and we need a specific risk assessment model. I think that is the main endpoint for this decade. We are doing the right job in the recurrence rate but we need to perform a better job in the bleeding risk assessment model, risk factor – it should be our focus this decade.

And another important data from Garfield, it is the pattern of how we were treating patients along the cancer journey, along the anticoagulation. And we can observe that the parenteral treatment is the treatment of choice in the first 30 days but this trend is kept at 3 months, at 6 months and 12 months. So parenteral treatment seems to be the treatment of choice in the beginning of diagnosis, at 3 months, at 6 months, at 12 months. At 12 months it is still the therapy of choice. The most common therapy used in cancer patients. Parenteral therapy seems to be an important tool to treat patients nowadays.

If we jump to the TESEO registry, I want to show you some data to finish. The first point is again the same data. Breast cancer is the third most common tumour included in TESEO. Low risk of tumour for VTE but a very prevalent tumour we have to take into account that these women can live for a very long period of time. Again amongst the 8 most common tumours in this registry are endometrial in the first position of this registry and I have to tell you that it is in endometrial cancer that is mainly diagnosed VTE in advanced disease. Very typical tumour for VTE but in the setting of advanced disease. Another important point is the stage. The stage is a very common risk factor for VTE. And we know the importance of stage in lung cancer, colorectal cancer – more than 75% of patients with lung cancer develop a VTE event in stage IV disease and almost 75% in colorectal. But this is not the case in breast cancer. In breast cancer 51% of the patients develop a VTE event with the localised disease. The localised disease means that we can cure these patients so the relevance of the stage depends on the type of tumour. And the stage in the breast cancer is very important in the localised, in the curable disease setting. So careful with breast cancers, we need a good risk assessment model to understand better the risk factor for breast cancer because we are going to have a large number of patients with VTE in localised disease. And again female a little bit lower incidence of occurrence 49.2% compared to male 50.8%.

And another important idea from TESEO, ovarian cancer and breast cancer have a different occurrence pattern. The patients face a higher long term risk compared to other tumours. We don’t only have peaks at 6 months but peaks over 20 or even 40 months that are related to the cancer biology and the cancer treatment. So longer surveillance, longer prophylaxis – these two tumours shouldn’t be considered as a pancreatic or gastric cancer. So different patterns of occurrence different, surveillance and maybe different prophylaxis.

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MAT-GB-2001012 (v6.0) Date of preparation: March 2022