Comparative assessment of low-molecular-weight heparins in cancer from the perspective of patient outcomes and survival

Figures & data

Figure 1 Anticoagulant mechanisms of unfractionated and low-molecular-weight heparins.

Table 1 Primary prophylaxis in the cancer patient: recommendations

Patient group	Recommended	Not recommended
Patients undergoing surgery	Prophylaxis with low-dose UFH or LMWH for at least 7–10 days Extended prophylaxis up to 4 weeks after discharge in patients with high-risk features	Contraindication to anticoagulation: consider mechanical methods alone
Hospitalized patients	VTE prophylaxis with anticoagulants	Contraindication to anticoagulation
Ambulatory patients receiving chemotherapy	Only patients with multiple myeloma receiving thalidomide or lenalidomide prophylaxis with LMWH or adjusted dose warfarin	All other patient categories

Abbreviations: LMWH, low-molecular-weight heparin; UFH, unfractionated heparin; VTE, venous thromboembolism.

Table 2 Comparison of the main characteristics of the commercially available LMWH cited in the article

LMWH	Method of depolymerization	Mean molecular weight (kDa)	Anti-Xa/anti-IIa ratio	Half-life (hours)
Dalteparin	Nitrous acid	6.0	1.9–3.2	2.3–2.8
Enoxaparin	Alkaline	4.5	3.3–5.3	4.0–4.4
Nadroparin	Nitrous acid	4.3	2.5–4.0	3.7
Tinzaparin	Enzymatic	6.5	1.5–2.5	3.0
Certoparin	Isoamyl nitrite	5.6	2.0–2.4	3.5
Bemiparin	Alkaline	3.6	8.0	5.2–5.4

Abbreviation: LMWH, low-molecular-weight heparin.

Table 3 Randomized clinical trials testing the effect of LMWHs on survival of cancer patients

Study	Cancer type	Control	LMWH (regimen)	Effect on survival^a
Altinbas et al^Citation76	SCLC	None	Dalteparin (5000 IU/day, 18 weeks)	+
FAMOUS^Citation75	Advanced cancer	Placebo	Dalteparin (5000 IU/day, 1 year)	+/− (+ patient with better prognosis)
MALT^Citation77	Metastasized and advanced cancer	Placebo	Nadroparin (therapeutic dose 2 weeks + half dose 4 weeks)	+/− (+ patient with better prognosis)
Sideras et al^Citation78	Advanced cancer	None	Dalteparin (5000 IU/day, 2 years)	+
INPACT^Citation82	NSCLC, prostate, pancreatic	None	Nadroparin (therapeutic dose 2 weeks + half dose 4 weeks, weight adjusted, followed by up to six cycles)	None
ABEL^Citation94	Limited SCLC	None	Bemiparin (3500 IU/day, 26 weeks)	+
TILT (ongoing, NCT 004775098)	NSCLC	Placebo	Tinzaparin (100 IU/kg once-daily, 12 weeks)	N/A

Notes:

a +, positive effect of LMWH on survival; N/A, results not yet available; +/−, inconclusive.

Abbreviations: LMWH, low-molecular-weight heparin; NCT, National Clinical Trial; NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer.

Figure 2 Antitumor properties of low-molecular-weight heparins. The rationale for an antitumor effect of anticoagulant drugs may rely on their capacity to inhibit blood coagulation. However, these agents, particularly heparins, exhibit the capacity to block hemostatic pathways specifically implicated in tissue malignant behavior, and show a number of coagulation-independent activities against cancer.

Table 4 In vitro studies exploring the effect of LMWH on tumor-induced endothelial cell angiogenesis

LMWH	Experimental model	Anti-angiogenic effect	LMWH mechanism proposed	Reference
Dalteparin	TCM-stimulated HMEC-1 and HUVEC	Inhibition of endothelial cell tube formation	Interference with bFGF and VEGF binding to their receptors	Marchetti et al^Citation85
	bFGF-stimulated HUVEC	Inhibition of endothelial cell tube formation and proliferation	Interference with bFGF binding to its receptor	Khorana et al^Citation86
Enoxaparin	bFGF-stimulated HUVEC	Inhibition of endothelial cell tube formation and proliferation	Interference with bFGF binding to its receptor	Khorana et al^Citation86
Tinzaparin	bFGF and TF/FVIIa stimulated HUVEC	Inhibition of endothelial cell tube formation	Increased release of TFPI	Mousa and Mohamed^Citation88
	bFGF-stimulated HUVEC	Inhibition of endothelial cell tube formation and proliferation	Interference with bFGF binding to its receptor	Khorana et al^Citation86
Bemiparin	TCM-stimulated HMEC-1	Inhibition of endothelial cell tube formation, proliferation, and wound healing	Interference with angiogenic factor binding to their receptor, increased released of TFPI	Vignoli et al^Citation87
Nadroparin	–	–	–	N/A
Certoparin	–	–	–	N/A

Note: Selected works from the literature on the commercially available LMWH cited in the article.

Abbreviations: bFGF, basic fibroblast growth factor; HMEC-1, human microvascular endothelial cell line-1; HUVEC, human umbilical vein endothelial cells; LMWH, low-molecular-weight heparin; N/A, not applicable; TCM, tumor-conditioned medium; TF, tissue factor; FVIIa, activated coagulation factor VII; TFPI, tissue factor pathway inhibitor; VEGF, vascular endothelial growth factor.

Figure 3 LMWHs inhibit endothelial angiogenesis induced by conditioned medium from pancreatic tumor cells. Endothelial cells were incubated with TCM from a human pancreatic carcinoma (MIA Paca2) cell line, in the presence or absence of 1 IU/mL LMWH bemiparin, dalteparin, and the ultra-LMWH Ro14. After 24 hours incubation, capillary-like tube formation was evaluated as previously described.⁸⁵ (A) The three heparins significantly inhibited the increase of tube formation induced by TCM. (B) Representative pictures of selected experiments showing the inhibition by the different heparins of pancreatic tumor cell-induced endothelial cell capillary-like tube.

Notes: Data are means + standard deviations of three experiments performed in duplicate. ^#P < 0.05 vs control; *P < 0.05 vs Paca2 CM.
Abbreviations: LMWH, low-molecular-weight heparin; TCM, tumor-conditioned medium.

Figure 4 LMWHs inhibit the proliferation/migration of pancreatic tumor cells. The human pancreatic carcinoma (MIA Paca2) cells were grown to confluence at 37°C in a 5% CO₂ atmosphere in incubator, wounded, and grown in presence or absence of 1 IU/mL LMWH bemiparin, dalteparin, and the ultra-LMWH Ro14. After 48 hours of incubation, the rate of proliferation/migration was evaluated as previously described.⁸⁷ (A) Heparins significantly affect the proliferation/migration features of pancreatic cancer cells. (B) Representative pictures of selected experiments showing the inhibition by the different heparins of proliferation/migration of pancreatic tumor cells.

Notes: Data are means + standard deviations of three different experiments performed in duplicate and are expressed as percentage of regrowth area, assuming the area occupied by cells in absence of fetal calf serum as 100% of regrowth. ^#P < 0.05 vs control; *P < 0.05 vs serum.
Abbreviation: LMWH, low-molecular-weight heparin.

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