Treatment and prophylaxis of thromboembolism in pancreatic cancer: influence on patient survival in western Algeria

Introduction

The links between venous thromboembolic disease (VTD) and cancer are very close. Indeed, the presence of cancer increases the risk of VTD by 6 times. Thrombosis can constitute the first manifestation (1,2). Cancers of the pancreas, stomach, central nervous system and lung are associated with VTD, with the risk increasing in metastatic forms and during the first months following the discovery of cancer (3). Pancreatic cancer (PC) is the seventh leading cause of cancer death worldwide, with an incidence rate of 4.2 cases per 100,000 population (4). In 1865, Armand Trousseau detected his own gastric cancer after contracting upper extremity venous thrombosis, which explained how migrating venous thrombosis can complicate cancer progression (5,6). It has been discovered that PC has a particular and unique potential to create a hypercoagulable state in patients, which is associated with clinically significant thrombosis, in addition to a number of patient-related risk factors, tumor factors, or treatment factors (7,8). Although, the postulated link between PC and hypercoagulability has stood the test of time, the pathogenic mechanisms involved, as well as the interplay between the many pathways involved, remain unclear (9).

The existing pharmacological options to prevent or treat thromboembolic complications without increasing the risk of hemorrhage are still insufficient. Moreover, available studies show a benefit of primary prophylaxis of thromboembolism (VTD) with low molecular weight heparins (LMWH) for advanced or metastatic PCs. It is therefore possible to offer it in these patients provided the risk of bleeding is low (10,11).

The objective of our study is to assess survival in patients with PC receiving thromboprophylaxis.

Methods

Population study

We conducted an observational, retrospective, descriptive and monocentric study in the Medical Oncology Department of the 1^st November 1954 Hospital of Oran over a period of 8 years, from 2014 to 2022. The data were collected from the patients’ medical records. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethical Board of Oncology Medical Oncology Department of the University Hospital Establishment November 1, 1954 Oran, Algeria. In Algeria, there is currently no text and laws to support scientific studies in scientific research. Therefore, we rely on obtaining written consent from patients or their legal guardians in the case of minors to participate in the study. We ensure that the involved subject fully understands the study’s objectives.

Our study population includes all patients with carcinoma of the pancreas, encompassing all stages, with or without thromboembolic disease. All patients were from western Algerian.

We done a clinical examination for all patients with a basic initial assessment, which includes radiological, anatomopathological and biological data. All patients received verbal and written information about the treatment and its side effects, and all patients signed a consent form.

Specific treatment with chemotherapy (according to the histological type, general condition and stage of the tumor), surgery (according to the location of the tumor and its respectability) or supportive care was assigned to patients who met the eligibility criteria and had consented to determine the therapeutic strategy.

Patients treatment

Patients will receive treatment based on curative LMWH if the initial radiological assessment confirms the presence of thromboembolic disease for an optimal period of 6 months and, at least, 3 month a minimum.

This treatment has been validated in the literature at the following dosages:

• Tinzaparin (Innohep^®) 175 IU/kg once daily;
• Enoxaparin (Lovenox^®) 150 IU/kg once daily.

If the radiological assessment does not indicate the presence of a thromboemolic disease, the patients will receive treatment based on preventive LMWH:

• Tinzaparine (Innohep^®) 3,500 to 4,500 IU/day, with a specific marketing authorization in surgery and medical oncology.
• Enoxaparin (Lovenox^®) 4,000 IU/day, with marketing authorization.

The patient and his entourage were informed of all the side effects of chemotherapy and anti-thromboembolic treatments before the first administration. Follow-up will be conducted periodically every 3 months through clinical, biological and radiological evaluation.

So, we observed 3 groups: patients with thromboembolic disease: receive curative LMWH treatment. Patients without thromboembolic disease: receive preventive LMWH treatment or none.

Statistical analysis

The data and statistical analysis will be conducted using IBM SPSS software version 25 with a prior check at entry using the program’s check module.

Descriptive analysis of data will involve transforming variables by grouping using either coding or conditional transformations for tabulation and analysis. The determination of 95% confidence intervals (CIs) around the mean, and the median (me) will be done for the risk α =0.05 for the quantitative variables. Survival analysis will be carried out using the Kaplan-Meier method.

Results

During the inclusion period, two hundred patients with PC were collected, but only 80 patients were included in our study. Our study population includes 45 men (56.2%) and 35 women (43.8%), with sex ratio of 1.2. The mean age of patients at diagnosis is 66.8±2.3 (min–max, 43–87) years with a median age of 66 years. Three patients have a history of another cancer (two with a history of colon cancer and one of breast cancer). Thirty-nine percent of the study population had a familial history of cancer (digestive and breast cancers). Forty-seven point five percent of our cohort are diabetic and 6.2% have a history of pancreatitis. Two patients had lower limb thrombosis before the discovery of their neoplasia and were under medical supervision after stopping the curative treatment of their thromboembolic disease. Alcohol is implicated in the etiopathology of PC. We found 5 patients consuming it occasionally (6.2%), and 25% are smokers. The average tobacco consumption was 12 packs per year.

More than two-thirds of our population (76.3%) are in good general condition with a performance index estimated at 1. In our population, 54% of patients presented tumors of the head of the pancreas, 30% at the level of the body and 16% located at the level of the tail of the pancreas, of which 91.3% are ductal adenocarcinomas. Fifty percent of tumors (T) classified as T3, 57.5% as N1 and 52.5% as M1.

For the treatment of our population, 87.5% received chemotherapy, 1.3% had radiotherapy concurrently with chemotherapy, and surgery was performed in 17.5% of our population (nine patients received surgical resection of the pancreatic tumor, including: 4 caudal duodenopancreatectomies, 3 left splenopancreatectomies, and 2 atypical surgical resections. For the other 5 patients, a biliary bypass was performed). During the course of the cancer pathology, the appearance of VTD was observed in 9 patients (11.2%). Two patients already had deep abdominal thrombosis. Eleven patients in our population had a VTD, which accounts for 13.7% of the total; 7 of them had an abdominal venous thrombosis, 3 patients had venous thrombosis in the lower limbs and only one patient had the thrombosis in the inferior vena cava. All these thromboembolic diseases were discovered either by abdominal computed tomography (CT) or by Doppler ultrasound of the lower limbs. These patients (n=11) received curative treatment for their established thrombosis and 33 (41.3%) patients received preventive treatment. The remaining 36 patients (45%) did not receive any treatment or prophylaxis for thromboembolic disease.

For the curative treatment in the 11 patients, 7 received sodium tinzaparin (Innohep) at the curative dose adapted according to the body mass index (BMI) and 4 patients received sodium enoxaparin (Lovenox) at the curative dose adapted according to the BMI.

For the preventive treatment administered to 33 patients, 23 patients received tinzaparin sodium (Innohep) at the preventive dose of either 3,500 or 4,500 IU and 10 patients received enoxaparin sodium (Lovenox) at the preventive dose adapted according to the BMI. The main characteristics of our patients are summarized in Table 1.

The evolution of the cancer in our study was marked by remission in 4 patients (5%) and relapse in 12 patients (15%). Nine patients (11.2%) are still undergoing systemic treatment. We observed that, more than half died of the overall population of study. Table 2 summarizes the characteristics of patients in the 3 groups who received or did not receive LMWH treatment.

The median overall survival of our population is estimated at 6±1.9 months. The mean overall survival is 9.2±2.28 months. The overall survival rate was estimated at 30% and 3% respectively at 1 year and 2 years (Figure 1). The best overall survival is found in patients without VTD with a mean survival of 9.5±2.4 months compared to a mean survival estimated at 7.1±3.8 months in patients with thromboembolic disease (P=0.40) (Figure 2).

Figure 1 Overall survival. EHUO Medical Oncology. Years 2014–2022. EHUO, Etablissement Hospitalier Universitaire Oran.

Figure 2 Overall survival according to the appearance of thromboembolic disease. EHUO Medical Oncology. Years 2014–2022. EHUO, Etablissement Hospitalier Universitaire Oran.

The best overall survival is found in patients who have received preventive anti-thromboembolic treatment, with a mean survival of 11.2±4 months. A mediocre mean survival for patients who received no treatment is demonstrated with 7.8±2.2 months. The median increases from 5±1.6 months in the absence of preventive treatment to 10±6.1 months after administration of the latter. The application of the Log-rank statistical test shows a borderline difference in terms of overall survival depending on the administration of preventive treatment for thromboembolic disease (P=0.050), illustrated in Figure 3.

Figure 3 Overall survival according to the taking of preventive treatment for thromboembolic disease. EHUO Medical Oncology. Years 2014–2022. EHUO, Etablissement Hospitalier Universitaire Oran.

Discussion

PC is one of the deadliest cancers with an increasing incidence (12). The 5-year survival rate, for all stages combined, is less than 8% (13). Patients with PC are at the highest risk of developing a VTD. The incidence of VTD varies from 5% to 41% depending on the series (13). The occurrence of VTD is associated with a reduction in overall survival (13,14).

International recommendations on the treatment and prevention of VTD in cancer have been published with the aim of standardizing and optimizing its management. They recommend the use of primary prophylaxis with LMWH (15). In our population, we identified the sex ratio at 1.2, which is consistent with the Moroccan population, where a sex ratio of 1.29 was found (16). A French population study conducted by Lubrano et al. found a male predominance with a sex ratio of 1.7 (17). The only Algerian population study by Bengueddach et al. demonstrated no difference in sex distribution (18).

The mean age of patients in our study was 66.8±2.3 years, with a median of 66 years. Similar results have been reported in several studies, such as those conducted by Frere et al. (19) and Muñoz Martín et al. (20), where the median age was 69 and 63.5 years respectively. We will compare our results with those of the observational, prospective study, multicenter BACAP-VTD which studied the occurrence of a venous thromboembolic events during the follow-up period of patients with PC, involving 731 patients (19).

The influence of alcohol and tobacco intoxication as epidemiological factors in the occurrence or aggravation of PC still controversial, it would seem that prolonged exposure is followed by demonstrated effects. In our cohort, 25% of the male population were smokers and 6.2% have chronic alcoholics. Alcoholism is higher in the BACAP-VTD study where the drinking population represents 26.6% and the smoking population represents 19.6%.

This difference is due to the difference in religion and customs between the two populations.

Moreover, the number of diabetic patients in our population compared to patients in the BACAP-VTD study was higher, representing 47.5% in our study. We demonstrated that the majority of patients were in good general condition (78.8%) compared to 89.5% in the other study, which were classified as World Health Organization (WHO) 0–1.

Regarding the tumor localization, in our data, 54% of the patients presented tumors of the pancreas’s head, 30% at the level of the body, and 16% located at the level of the tail. The head of the pancreas represents the preferred site for the occurrence of PC. The same result was founded in the comparative study with 58% of tumors located at the cephalic level.

Regarding the histological nature of the tumor, pancreatic adenocarcinomas were found in 91.3% of patients. There was a predominance of this histological type, which constitutes the common denominator of this type of cancer.

For the staging of the disease, our work highlights the frequency of locally advanced and metastatic stages at 93%. This rate is around 56.4% in the BACAP-VTD study. All these rates are only a reflection of the delay in the diagnosis of pancreatic carcinoma, which is still relevant.

Among all patients, only 17.5% received surgery and 1.3% received concomitant radiochemotherapy. The majority of patients received chemotherapy, showing that the locally advanced and metastatic stages are in the majority in our study (87.5% of patients received this chemotherapy). The most used protocol is gemcitabine in these two cases (44.2%). These data are in agreement with two points with the data of the BACAP-VTD study, the percentage of patients treated by radiochemotherapy, which is the same at 1.3% and the use of gemcitabine in the treatment of their patients at a rate of 39.1% (the most used protocol). On the other hand, there was more surgery (31.3%) and less chemotherapy (59.1%) compared to our study, showing that they have more localized stages (43.6%).

During the evolution of the cancer pathology, the appearance of venous thromboembolism was observed in 9 patients (11.2%) of our population of study. However, 2 patients already had deep abdominal thrombosis discovered during the initial assessment of the disease. A total of 11 patients in our population had a VTD (13.7%). Results of the BACAP-VTD study with a median follow-up of 19.3 months report that 21% of patients presented with venous thromboembolic event. This difference found between the two studies can be explained by the small sample size of our series, or given the strategy of prescribing an LMWH prophylactic from the outset in patients with PC before starting chemotherapy, 41.2% of patients were put on preventive LMWH. In the BACAP-VTD study, there was a visceral thromboembolic event in 29.61% of cases, deep vein thrombosis in 26.32% of cases and pulmonary embolism in 17.11% of cases (19). In our study, there was no pulmonary embolism or visceral thrombosis. On the other hand, 64% had deep vein thrombosis.

The comparative study also shows that the occurrence of thromboembolic events has a pejorative prognostic impact, with a significant decrease in the medians of overall survival (which decreased from 14.5 to 9.13 months). We found in our study that the results were not significant probably due to the reduced sample size of our study. On the other hand, there was a significant improvement in the overall survival of our patients.

A preventive treatment was administered with a median which increased from 5 to 10 months (P=0.050).

All of these data suggest the interest of proposing an adequate thromboprophylaxis by LMWH, as recommended in patients with locally advanced PC or metastatic disease, receiving systemic treatment (21).

The most important limitation of our study could be the small sample size. The main influence of a small sample size is on statistical power: as sample size increases, the power increases.

Risk factors are poorly established apart from family history and tobacco (22). In CP patients with PC, the occurrence of an episode of VTD is a frequent event, especially at the locally advanced and metastatic stages of the disease and during courses of chemotherapy (23). It is associated with reduced overall survival. Through our study, the best overall survival was found in patients who took preventive anti-thromboembolic treatment with an average survival (24).

Conclusions

This study reveals that thromboembolic disease significantly affects survival in patients with PC. With a median overall survival of only 6 months, our findings show that patients without thromboembolic events had a mean survival of 9.5 months, compared to 7.1 months for those with such complications. Additionally, preventive anti-thromboembolic treatment was associated with improved survival rates, highlighting its potential benefit in this patient population. These results emphasize the importance of early recognition and management of thromboembolic risks to enhance patient outcomes in PC management. Further studies are needed to refine treatment protocols and validate these findings. Therefore, prospective randomized studies will be necessary to confirm these observations.

Acknowledgments

We are very grateful to the patients who were accepted to participate to this study.

Footnote

Data Sharing Statement: Available at https://apc.amegroups.com/article/view/10.21037/apc-24-18/dss

Peer Review File: Available at https://apc.amegroups.com/article/view/10.21037/apc-24-18/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apc.amegroups.com/article/view/10.21037/apc-24-18/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethical Board of Oncology Medical Oncology Department of the University Hospital Establishment November 1, 1954 Oran, Algeria. In Algeria, there is currently no text and laws to support scientific studies in scientific research. Therefore, we rely on obtaining written consent from patients or their legal guardians in the case of minors to participate in the study. We ensure that the involved subject fully understands the study’s objectives.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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