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FACTORS ASSOCIATED WITH LOWER LIMB DEEP VEIN THROMBOSIS IN

CANCER OF THE BREAST PATIENTS ON CHEMOTHERAPY AT A SUB-SAHARAN
AFRICAN CANCER CENTRE FACTORS ASSOCIATED WITH LOWER LIMB D...

Article in East African Medical Journal · April 2021

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3698 EAST AFRICAN MEDICAL JOURNAL April 2021

East African Medical Journal Vol. 98 No. 4 April 2021

FACTORS ASSOCIATED WITH LOWER LIMB DEEP VEIN THROMBOSIS IN CANCER OF THE BREAST
PATIENTS ON CHEMOTHERAPY AT A SUB-SAHARAN AFRICAN CANCER CENTRE
Gamukama Tuhaise, MB ChB, M.MED Surgery, Department of Surgery, College of Health Sciences, ,
Makerere University P.O. Box 7072, Kampala, Uganda. Makumbi Kabanda Timothy, MB ChB, M.MED
Surgery, MBA, Dip Emergency, Senior Lecturer, , Department of Surgery College of Health Sciences,
Makerere University, P. O. Box 7072, Kampala, Uganda. Ocen William, MB ChB, M.MED Surgery, MBA,
Senior Consultant, Mulago National Referral Hospital, Senior Lecturer, Lira University, P.O. Box 1035, Lira,
Uganda.

Corresponding author: Gamukama Tuhaise, MB ChB, M.MED Surgery, Department of Surgery, College
of Health Sciences, Makerere University P.O. Box 7072, Kampala, Uganda,email, [email protected]

FACTORS ASSOCIATED WITH LOWER LIMB DEEP VEIN THROMBOSIS IN

CANCER OF THE BREAST PATIENTS ON CHEMOTHERAPY AT A SUB-
SAHARAN AFRICAN CANCER CENTRE

G. Tuhaise, M. K. Timothy and O. William

ABSTRACT

Background: Cancer and its treatments are well recognized risk factors for venous
thromboembolism. Venous thromboembolism in breast cancer is common, and
this is related to its high prevalence among women worldwide. Studies of
thromboembolic events in a background of cancer treatment in various setting
provide information relevant for forestalling some of the complications. The study
was set out to determine the factors associated with lower limb deep vein
thrombosis in breast cancer patients undergoing chemotherapy at a tertiary cancer
treatment center in Uganda.
Methods: this was a descriptive and cross-sectional study
Results: Of the 98 breast patients recruited 95 (97%) were female and 3(3%) males.
The mean age was 48 years while 4(67%) were above 60 years. Most, 86 (88%) had a
performance status of 0, and with body mass index of 20.3. Deep vein thrombosis
was demonstrated in 6 (6.1%) breast cancer cases evaluated. These 6 had in addition
other comorbidities; 3 (50%) diabetes mellitus, 3 (50%) hypertension, 4(67%) had
edema of the lower limbs, while 2(33%) had lower limb discoloration.
Conclusion: Deep vein thrombosis in breast cancer patients on chemotherapy
affected 6% of the patents and the associated factors were age of more than 60 years,
and edema of the lower limbs. Recommendation: there is need to look for deep vein
thrombosis when patients have the lower limb edema. Furthermore, increased
index of suspicion when more cases of breast cancer on chemotherapy are studied.
 April 2021 EAST AFRICAN MEDICAL JOURNAL 3699

INTRODUCTION regimen of cyclophosphamide(C),

methotrexate (M), 5‐fluorouracil (F) (9).
Venous thromboembolism (VTE) which Reports on the effects of classical and
consists of deep vein thrombosis (DVT) and its modified adjuvant CMF-chemotherapy
complication pulmonary embolism is among showed that this chemotherapy is able to
the three leading causes of cardiovascular induce alterations in markers of coagulation in
disease. It is the second leading cause of death breast cancer patients(10)(11). Hormonal
in patients suffering from malignant agents used in breast cancer too have
tumors(1)(2). Venous thromboembolism is thrombogenic properties. In a randomized
associated with severe morbidity and controlled trial of 1312 patients, those
significant mortality, mostly owing to receiving adjuvant treatments with Tamoxifen
pulmonary embolism which occurs in about had a two-fold thrombotic risk compared to
30–40% of patients with venous thrombosis. those who received aromatase inhibitors(12).
About 60–70% of patient with symptomatic In another study, premenopausal women
venous thrombosis are due to deep vein receiving chemotherapy and Tamoxifen had
thrombosis(3). Cancer has become a well- significantly more thrombotic complications
recognized risk factor for venous than those receiving only chemotherapy (13).
thromboembolism and accounts for about 18% Although it is widely accepted that
of all incident thrombotic events occurring this development of venous thromboembolism is
category of breast cancer patients (4). The risk multifactorial, the increased rate of
of venous thromboembolism is increased six to chemotherapy-induced thromboembolism
seven folds in cancer patients, especially those occurring in advanced breast cancer patients
receiving chemotherapy (5). as compared with adjuvant patients suggests
In the developed world, breast cancer that other mechanisms may be occurring in the
patients are known to have lower risk for former group. There is paucity of data about
venous thromboembolism compared to venous thromboembolism among breast
pancreatic, hematological and pelvic cancer cancer patients in sub-Saharan Africa and yet
patients (6). However, being the most there is significant burden of breast cancer
prevalent cancer in women worldwide, breast disease (14). In this study, we aimed to
cancer related venous thromboembolic events determine the prevalence of lower limb deep
cause a big burden to patients and hence vein thrombosis among breast cancer patients
strains medical resources (7). undergoing chemotherapy.
Venous thromboembolism following breast
cancer chemotherapy is not uncommon. In MATERIALS AND METHODS
early breast cancer, venous thromboembolism
occurs in 5–10% of patients receiving Study setting: The study was conducted at
chemotherapy with a mortality of 0.2–0.5% (8). Uganda cancer institute (UCI), Kampala,
Whereas, breast cancer patients with stage IV Uganda from November 2018 to April 2019.
disease showed incidences of venous This institute is a specialized public, research,
thrombosis of 18% and mortality rates of 9% and cancer treatment unit affiliated to
especially those treated with a chemotherapy Makerere University School of medicine and
Mulago National Referral Hospital. It is
3700 EAST AFRICAN MEDICAL JOURNAL April 2021

located along upper Mulago hill road, on department. The scan report was written,
Mulago hill, Kawempe division of the images saved on compact disks and findings
Kampala city, Uganda. It has an inpatient filled in the questionnaire for completion. For
capacity of 80 beds and attends to over 200 those with evidence for DVT, the patient was
outpatients daily. Cancer patients from taken to the hematologist for prescription.
various parts of the country and neighboring Data management: Data was coded and entered
countries like South Sudan, Kenya and Congo into EPI DATA version 3.1, then exported to
are referred to the institute with histology STATA College Station TX version 14.0 for
reports showing evidence of cancer or when analysis. Descriptive statistics were computed,
very suspicious for cancer. Staging the non-parametric Fischer exact test at 5%
investigations and schedules for the oncologist level of significance was used to establish the
review are done at the institute, then initiated association between categorical variables.
on the cancer treatment protocols. The breast Odds ratios with 95% confidence intervals
cancer treatment protocol chemotherapy regimens; were also computed. The variables established
Neo-adjuvant or adjuvant chemotherapy for to be statistically significant at bivariate stage,
Her2 negative breast cancer is CAF as were included in a step wise multivariate
preferred regimen then CMF, FEC, dose dense analysis.
AC, or TAC. The Her2 positive breast cancer Ethical consideration: This study was conducted
patients receive TCH as preferred regimen or with the approval of the School of Medicine
dose dense AC. A-Adriamycin, C- Research and Ethics Committee of Makerere
cyclophosphamide, E-Epirubicin, F- University, College of Health Sciences (#REC
5flourouracil, H – transtuzumab, M- REF 2018-151), and administrative clearance
Methotrexate, and T-Docetaxel. from Uganda cancer institute (SR: 109).
Study design: This was a descriptive cross-
sectional study. RESULTS
Study eligibility criteria: Both female and male
with histology confirmed breast cancer and The study enrolled 98 participants, 95(97%)
scheduled chemotherapy. Availability of females and 3 (3%) males. The average age was
complete medical information and signed 48 years and range 18-72, and body mass index
informed consent. was 20.3 (range of 15-27). The ECOG
The sample size was determined using Kish performance; 86 (88%) status of 0.
and Leslie formula, sample size correction for Out of the 98 breast cancer patients, 6 had
finite population and an online A priori thrombi in the lower limbs prevalence of 6.1%
calculator by Daniel Soper which established a with 95% CI (2.7, 13.1). All the 6 breast cancer
sample size of 98 participants. patients with deep vein thrombosis were
Sampling frame: Nonprobability consecutive females, and on CAF as the chemotherapy
sampling technique was used. regimen (Table 1). There were 14 veins that
Procedure of recruitment and Patient flow: The had thrombi in them, of which both the
data was filled in a preformed questionnaire as proximal and distal limb veins had 7(50%)
the patient was being taken through the each. Out of the 6 patients with deep vein
evaluator processes. The procedures in thrombosis, 4(67%) were above 60 years of age,
assessment included the patient taken for a 3 (50%) were diabetic, 3 (50%) were
venous duplex scanning at the radiology hypertensive, 4(67%) had edema of the lower
 April 2021 EAST AFRICAN MEDICAL JOURNAL 3701

limbs and 2(33%) had limb discoloration analysis were then include in a multivariate
(Table 2). analysis. Upon fitting these factors, using
The logistic regression analysis was binary logistic regression model with stepwise
conducted to assess factors that explain the elimination method only one variable was
occurrence of deep vein thrombosis, variables retained. The variable was lower limb edema
with P< 0.2 from the bivariate regression with P< 0.001 (Table 3).

Table 1
Characteristics of patients with deep vein thrombosis
Study Age Sex ECOG BMI Chemo Chemo Cancer History Breast Edema
No. Type cycles Stage of DM surgery
1. 66 F 1 18 CAF 6 IV Yes Yes No
2. 65 F 0 16 CAF 6 IV Yes No Yes
31. 63 F 0 17 CAF 6 1V Yes No Yes
42. 72 F 2 18 CAF 6 IIIB No Yes Yes
47. 28 F 0 23 CAF 1 III No No No
89. 38 F 0 23 CAF 3 IV No No Yes

Table 2:
Prevalence of Deep vein Thrombosis across the variables
Variable Deep Vein Thrombosis Present Fischer Exact test
No n=92 (93.9%) Yes n=6 (6.1%) P value
Sex
Male 3 (100) 0 (0) 1
Female 89 (93.7) 6 (6.3)
Age Category
<30 3 (75) 1 (25) 0.002
31-60 66 (99) 1 (1)
>60 13 (76.5) 4 (23.5)
Body Mass Index (BMI)
</= 18 25(86) 4 (14) 0.765
18.5-25 65(97) 2(3)
>25 2(100) 0
Smoking status
Never 86 (94.5) 5 (5.5) 0.087
Ex-smoker 6 (85.7) 1 (14.3)
Alcohol use
Never 59 (96.7) 2 (3.3) 0.195
Current/Stopped 33 (89.2) 4 (10.8)
Diabetes
No 85 (96.6) 3 (3.4) 0.013
Yes 7 (70) 3 (30)
3702 EAST AFRICAN MEDICAL JOURNAL April 2021

Hypertension
No 69 (95.8) 3 (4.2) 0.188
Yes 23 (88.5) 3 (11.5)
Post-Surgery
No 38 (90.5) 4 (9.5) 0.087
Yes 52 (96.3) 2 (3.7)
Limb Edema
No 88 (97.8) 2 (2.2) <0.001
Yes 4 (50) 4 (50)
Limb Discoloration
No 85 (95.5) 4 (4.5) 0.093
Yes 7 (77.8) 2 (22.2)

Table 3
Results of Simple and Multiple Logistic Regression
Simple Multiple
OR (95% CI) p value OR (95% CI) p value
Age Category
</=60 1 1
>60 12.15 (2.02, 73.22) 0.006 7.3 (0.86, 61.88) 0.068
Smoking
Never 1
Ex-smoker 2.87 (0.29, 28.62) 0.37
Alcohol use
Never 1
Current/Stopped 3.58 (0.62, 20.58) 0.154
Diabetes
No 1 1
Yes 12.14 (2.06, 71.73) 0.006 3.37 (0.33, 34.09) 0.303
Hypertension
No 1
Yes 3 (0.57, 15.91) 0.197
Post-Surgery
No 1
Yes 0.15 (0.02, 1.31) 0.086
Limb Edema
No 1 1
Yes 44 (6.13, 315.85) <0.001 20.12 (2.17, 186.62) 0.008
Limb discoloration
No 1
Yes 6.07 (0.94, 39.16) 0.058
 April 2021 EAST AFRICAN MEDICAL JOURNAL 3703

DISCUSSION compared to post-menopausal women among

breast cancer patients in Africa(17), and this
This study results are in agreement with differs slightly from European data of having
Sally’s and a Ugandan study by Gakwaya et al, the majority of breast cancer patients as post-
2008 that breast cancer is found majorly in menopausal women(18).
women below 50 years in Uganda(15). In One large study, conducted in England by
addition, the findings of prevalence of lower Alex J et al 2015, using data of 13,202 breast
limb deep vein thrombosis was 6.1% with cancer patients showed that age > 65 years,
confidence interval of (2.7, 13.1) is consistent metastatic disease, BMI > 40, history of
with other previous studies. Reasons for surgery, having more than 3 comorbidities, use
patients with advanced/metastatic breast of chemotherapy and hormonal therapy were
cancer having higher rates of deep vein reported to be factors that increase occurrence
thrombosis include vascular and lung of both deep vein thrombosis and pulmonary
involvement. Non-ambulatory patients are at a embolism(7). It is however evident in our
greater risk than outpatients due to blood study that few variables of; age, comorbidities
stasis, and hence this could explain the low and clinical signs showed predictability at
prevalence in this study. However, this study bivariate analysis but not at multivariate
evaluated ambulatory patients. When analysis. This defers from the western data, but
compared to other outpatient studies like it could be due to the small sample size, or the
Khorana et al, 2013 our prevalence is higher difference in subtypes of cancer between
than other studies ((16). Africans and the Europeans that is known.
Our study assessed whether age, body mass Study limitations: this study was not able to
index, comorbidities, performance status, and evaluate for other associated factors due to
clinical signs were associated with deep vein missing data in patient files on the grade and
thrombosis among breast cancer patients. stages of the breast cancer disease. In addition,
Lower limb edema with P= 0.008 was the only this being a cross-sectional study, we were
statistically significant variable in our setting unable to correlate the temporal component on
after multiple logistic regression. Age, and the formation of thrombi with chemotherapy
diabetes were eliminated at multivariate and breast cancer disease.
analysis, while the other variables of BMI, and
performance status were eliminated at CONCLUSION
bivariate analysis because of not showing any
associations with occurrence of deep vein Deep vein thrombosis prevalence is 6%t
thrombosis. among breast cancer patients on
It is observed that the average age was 48 chemotherapy, we recommend screening
years, ranging from 18 to 72 years and this is in patients during the chemotherapy period for
keeping with several studies that show breast early detection.
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