During 2012, it was found that there were about 1.82 new lung cancer cases and around 1.59 million lung cancer deaths worldwide ²¹. Approximately four out of five cases are men. Although the incidence is decreasing in men, it is still the most important cause of cancer death. In women, the incidence is increasing. More than 85% of lung cancers are associated with smoking. The median survival following diagnosis is eight months, and 13% of patients are still alive after five years ²². Only 25% of patients are eligible for an intentionally curative treatment, such as tumour resection. In this group, the cure rate is about 25%. The remaining patients are not eligible for resection due to locoregional or metastatic spread of disease, or their overall state of health ²³. Despite diagnostic and therapeutic advances, the stage distribution and survival rate for patients with NSCLC has not improved substantially in accordance with this advancement ²⁴.

Non-small cell lung cancer (NSCLC) is a major health problem all over the world ^{25, 26}. Surgery represents the mainstay treatment in stages I-II, and in some patients with stage IIIA (i.e. patients with minimal N2 or T3N1 disease). Stage IIIA, includes a heterogeneous group of patients who are usually offered a multimodal approach including surgery and/or chemotherapy and/or radiotherapy. The 5-year survival rates after surgery are satisfactory only in pT1N0 disease, 70 to 90% ^{20, 21}, whereas they fall in more advanced stages: values of 57%, 55%, 39%, and 38% have been reported in T2N0, T1N1, T2N1, and T3N0 disease, respectively ²⁷. In stages IIIA-B, the survival rate is even lower in spite of aggressive treatments ^{27, 29, 30}.

Adjuvant radiation therapy failed to demonstrate any significant improvement in survival rates: although radiotherapy would increase the rate of local control of the disease, there is no convincing evidence that it increases the distant control or the survival. In addition it was associated with a significant increase of death. The real impact on survival of adjuvant chemotherapy remains unclear in spite of several randomized clinical trials ³¹.

The impact of neo-adjuvant chemotherapy remains controversial. A Spanish study ³² and a US randomized study ³³ on neo-adjuvant chemotherapy in N2 disease showed an increased survival in the study arm of combined treatment. However, the survival rate of patients undergoing surgery alone was extremely poor in both studies. In another study conducted in France ³⁴ the administration of two courses of chemotherapy followed by surgery was compared to surgery alone in resectable stage I-IIIA NSCLC; a trend toward a survival advantage not reaching significance (p = 0.11) was observed. In addition, when the data were analyzed according to the nodal status, the survival advantage was significant in N0-N1 disease but not in patients with N2 disease.

Over time, new anticancer agents, molecular-targeted agents became available for clinical studies. In particular, monoclonal antibodies and small molecules targeted to epidermal growth factor receptor were evaluated in a randomized setting of patients with advanced disease; but no survival advantage could be achieved by using these biological agents, combined with standard chemotherapy, in the whole group of enrolled patients ³⁵.

Local recurrence and distant metastasis have to be considered as the leading cause of treatment failure in resected NSCLC. The failure pattern in operated NSCLC depends on the stage of the disease; while the local control is very satisfactory in stages IA-B ^{28, 36}. It is not the case in more advanced stages as they have a higher risk of local recurrence. In particular, the recurrence rate is relatively low in stage II ³⁷, but increases in stage IIIA, especially in N2 disease ³⁸. Overall, distant metastasis has to be considered as the leading cause of treatment failure in resected NSCLC. As a consequence, it is reasonable to hypothesize that the prevention of the metastatic spread (preoperatively, peri-operatively, and postoperatively) could represent the mainstay of improvement in chances of cure in those patients. Blood clotting components in micro vessels were found to play a significant role in the process of metastasis ³⁹.

It has been recognised that venous thrombo-embolism (VTE) represents a common complication of malignancy. It was shown that the relative risk of VTE is increased about 4-6 folds in patients with cancer, compared to sex and age matched control ⁴⁰. Previous studies have also showed that the development of symptomatic VTE in a cancer patient is associated with significant reduction of the overall survival ⁴¹.

The clinical importance of anticoagulant therapy in patients with cancer is readily apparent, in view of the prevalence of VTE in cancer patients, and its associated morbidity and mortality. Generally, in non-cancer patients, the acute VTE is treated with anticoagulants starting by using the unfractionated heparin (UFH) or low molecular weight heparin (LMWH) for a period ranging from 5 to 7 days followed by oral anticoagulation via warfarin for at least 3 months. ⁴².

The use of LMWH has particular advantages over UFH, many of which are of great importance to cancer patients ⁴³. Firstly, The LMWH has a significantly longer half-life than UFH, so can be administered once daily as subcutaneous injection. Secondly, due to its more predictable pharmacokinetics, it could be used without frequent laboratory monitoring ⁴⁴. Finally, both heparin-induced thrombocytopenia (HIT), and heparin–induced osteoporosis are both less common with LMWH compared with UFH ⁴³. Consequently, LMWH have become widely used as the treatment of choice for the management of acute VTE in cancer ⁴⁵. However, it remains unclear whether different LMWH preparations are equally efficacious and also the optimal dose of LMWH dosage regimen should be defined in this setting ⁴⁶.

The use of warfarin therapy in patients with cancer could be associated with important clinical problems like gastrointestinal disturbances, or hepatic dysfunction. Moreover, the concurrent chemotherapy can lead to significant fluctuation in International Normalized Ratio (INR). Consequently, establishing a stable INR within the target therapeutic range is more difficult. The risk of warfarin induced major bleeding will also be further exacerbated during any period of chemotherapy induced thrombocytopenia ⁴⁷ In view of inherent difficulties associated with warfarin use in oncology patients, recent studies have evaluated the efficacy and safety of long term LMWH as an alternative to warfarin. All trials performed with different types of LMWH demonstrated a comparable long term efficacy in comparison to warfarin in cancer patients ⁴⁸.

The pathogenesis of cancer related VTE is complex, involving multiple interactions between malignant cells, endothelial cells and coagulation cascades. Tumours can significantly impact upon all three components of Virshow’s triad. These different mechanisms have been comprehensively discussed in another published review ⁴⁹. One of the most important mechanisms through which cancer induced coagulation cascade activation is due to apparent tissue factor (TF) expression on tumour cell surfaces (including pancreatic cancer, non small cell lung cancer, and leukemia) ⁵⁰.

Platelet aggregation or fibrin coagulation may facilitate the tumor cell evasion of destruction by natural killer cells. Heparin increases the clearance of the tumor cells from the blood in mice and has an anti-metastatic effect ⁵¹ through making tumor cells more susceptible to NK lymphocytes ⁵². Moreover, there is clear evidence that the arrest of the tumor cells in capillaries is related to the development of micro-thrombi ⁵³. Meanwhile, the thrombin affects directly the tumor cells to become more adhesive.

Tilley R. et al. demonstrated that activated coagulation proteases interact with protease activated receptors (PARs) on tumour and host vascular cells, leading to induction of genes involved in apoptosis, angiogenesis, and metastasis ⁵⁰. The role for TF expression was reported in determining the progression of tumour growth and angiogenesis ⁵⁴. The studies performed on animal models (rats inoculated with Walker 256 carcinosarcoma cells plus warfarin therapy for ten days), suggested that oral vitamin K antagonists could significantly reduce pulmonary metastases (98% vs. 85.8%; p < 0.001) and improved overall survival. Same results were encountered with other different malignant cell lines including B16 melanoma cells, KHT tumour transplant ⁵⁵. In contrast, warfarin therapy was found not to enhance the cytotoxic or anti metastatic effects of 5-flurouracil in murine models of adenocarcinoma or L210 leukemia, respectively ⁵⁶.

In a study conducted by Zacharski et al.⁵⁶ to test the effects of warfarin effect on survival of cancer patient (head and neck, prostate, colorectal and lung), Warfarin therapy did not improve overall survival for patients with colorectal, prostatic, or head and neck tumours. However, subgroup analysis demonstrates a significant effect of warfarin on overall survival in patients with small cell lung cancer (SCLC).

Several randomized clinical studies have tested the effect of heparin on survival in different types of cancer (small cell lung cancer “SCLC”, breast, GIT, pancreas, gut, ovary, uterus, renal, colorectal and prostate). One study conducted by Lebeau et al. on survival in patients with both, limited and extensive SCLC who received UFH documented better complete response rates (37% vs. 23%; p = 0.004) and better median survival (317 days vs. 261 days; p = 0.01). A subgroup analysis demonstrated that a significant beneficial effects of UFH in patients with limited stage SCLC rather than those with more extensive disease (p = 0.03)(57-61).

In order to investigate whether the LMWH influences survival in cancer patients without VTE, the FAMOUS (Fragmin Advanced Malignancy OUtcome Study) trial enrolled 385 patients with histologically confirmed advanced (stage III and IV) malignant disease of different types of cancer ⁵⁹. All patients had a minimum predicted life expectancy of three months, and received chemotherapy ^32% and or radiotherapy (8%) at the discretion of the treating physician. Moreover, patients were randomized to receive LMWH (Dalteparin) 5000 IU daily or placibo for 12 months. A non significant trend towards a survival advantage was observed in the group of patients treated with Dalteparin. In MALT (Malignancy And Low molecular weight heparin Therapy) study, there was a significant improvement in overall survival in those patients randomized to receive Nadroparin therapy compared to control group. Furthermore, the beneficial effects of LMWH therapy were again higher in the subgroup of patients who had longer life expectancy (more or equals to 6 months) at enrolment ⁶⁰. A third study conducted by Sideras et al. has further investigated the effects of LMWH on survival in patients with advanced solid tumours ⁶¹. In contrast to the previous two studies, this study did not show any effects of LMWH on overall survival even in the subgroup that had better prognosis.

Different coordinated steps are essential to evolve cancer and its metastases ⁶². These steps include 1) cell cancer proliferation; 2) establishment of a defence against attacks of the immune system; 3) angiogenesis; 4) cancer cell migration after detachment from their original site; 5) adhesion and invasion of surrounding tissues; 6) access of cancer cells to blood and lymph vessels with consequent adhesion and invasion of the lining endothelium giving the opportunity for colonisation at distant sites ^{62, 63}.

Heparin can inhibit proliferation of different cell types. The anti-proliferative effects of heparin were attributed to their inhibitory effects on the proto-oncogenes as c-fos and c-myc through alterations of the protein kinase C-dependant signal transduction pathway ^{62, 64}. It was shown that heparin inhibits phosphorylation of the mitogen activated protein kinase (MAPK), which is an intermediate kinase in the protein kinase C-signaling cascade ^{65, 66}. However, the results of the few studies that evaluated the effect of heparin on proliferation of cancer cells were inconclusive ^{61, 66, 67}.

Heparin can affect adhesion of leucocytes to endothelium at sites of inflammation or tumor invasion; hence it can interfere with the immune reactions. Moreover, heparin can inhibit leukocyte activation and affect complement activation ⁶⁸. In addition to the direct effect of heparin on the immune system, Gorelik et al.⁵¹ has suggested that heparin inhibits metastasis by rendering cancer cells more vulnerable to cytotoxic effects of natural killers (NK) cells.

In short, heparin could affect the immune system directly by inhibiting the complement system and extra-vasation of the leukocytes. Consequently, it enhances the susceptibility of cancer cells to immunological attacks ⁶².