Lung cancer research

Key words: low-molecular weight heparin; lung cancer; outcome; recurrence; surgery

Abbreviations: LMWH = low-molecular-weight heparin; NSCLC non-small cell lung cancer; UH = unfractioned heparin; VTE = venous thromboembolism

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N on-small cell lung cancer (NSCLC) represents a major public health problem worldwide. In western countries, lung cancer deaths range from 5 to 27/100,000 in women to 25 to 77/100,000 in men, and its incidence is thought to be very close because of the high case-fatality rate of the disease. (1,2)

As far as treatment is concerned, surgery represents the mainstay in stages I-II, and in some subsets of patients with stage IIIA (ie, patients with minimal N2 or T3N1 disease). Stage IIIA, however, includes an 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, with figures of approximately 70 to 90%, (3-6) 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. (3) In stages IIIA-B, the survival rate is even lower in spite of aggressive treatments. (3,7-11)

If we look beyond surgery, the therapeutic advances achieved during the last 30 years, even if tangible, have had only a modest impact on the overall survival. 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. (12) A metaanalysis (13) of the results of postoperative radiation therapy in 2,128 patients treated in nine randomized trials concluded that this treatment was associated with a highly significant increase in risk of death.

The real impact on survival of adjuvant platinum-based chemotherapy remains unclear in spite of several randomized clinical trials. Recent results of the Adjuvant Lung Project Italy trial, (14) including 1,088 patients randomized to receive either chemotherapy (cisplatin, mytomycin C, vindesine) or not after radical surgery for stages I-IIIA NSCLC, showed no differences in survival in the two groups. However, the results of the International Adjuvant Lung Cancer Trial (15) showed a little (4%) but significant impact in terms of long-term survival for patients receiving adjuvant chemotherapy. The impact of neoadjuvant chemotherapy remains controversial. A Spanish study (16) and a US randomized study (17) on neoadjuvant chemotherapy in N2 disease showed an increased survival in the study arm of combined treatment. It is of note, however, that the survival for patients undergoing surgery alone was extremely poor in both these studies. However, in a French study, (18) 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, but a severe perioperative toxicity was often experienced in the combined study arm. Furthermore, 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.

In the last decade, new anticancer, 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. (19) Though a small undefined subset of patients seems to benefit from these drugs, no survival advantage could be achieved by using these biological agents, combined with standard chemotherapy, in the whole group of enrolled patients. (19)

By considering this scenario, it doesn't seem realistic to foresee tiny marked improvement in the survival of patients with NSCLC in the coming years, even in those with resectable disease. However, if we look at the natural history of operated NSCLC, we have to consider that the pattern of failure depends on the stage of the disease. The local control is, in fact, very satisfactory in stages 1A-B, (4,20) whereas more advanced stages carry a higher risk of local recurrence. In particular, the recurrence rate is relatively low in stage II, (21) but increases in stage IIIA, especially in N2 disease. (22,23) Overall, distant metastatic spread 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, perioperatively, and postoperatively) could represent the mainstay of improvement in chances of cure in these patients. The process of metastatic colonization by the primary tumor involves several distinct steps and mechanisms, but it is well known that the components involved in blood clotting contribute to the systemic spread and/or successful implantation of metastatic cancer cells, but probably through different mechanisms. (24) We therefore believe that a strong rationale supports the investigation of drugs possibly inhibiting metastatic spread via the interference in the blood-clotting pathway. What is more, both unfractioned heparin (UH) and low-molecular-weight heparin (LMWH) seem to favorably affect the outcome of patients with cancer receiving prophylaxis or treatment of deep venous thrombosis. (25,26) Although it is possible that the favorable impact on survival is related to the antithrombotic mechanisms, there is sufficient experimental and preclinical evidence that both UH and LMWH have an anticancer effect via different mechanisms (24-26) We therefore suggest that trials on long-term administration of LMWH in patients with operable NSCLC should be initiated as soon as possible, in the attempt to improve the outcome of this neoplasm, whose prognosis continues to be unsatisfactory (except in stage IA disease) in spite of complete resection and, possibly, adjuvant or neoadjuvant treatments.

RATIONALE FOR CLINICAL TRIALS

Heparins are effective in both prevention and treatment of venous thromboembolism (VTE). As patients with cancer have an increased risk for this potentially lethal complication, the use of heparins may favorably affect outcomes simply by reducing the risk of VTE. (25,26) However, a growing amount of data has appeared in the literature suggesting that heparins may have other antitumor actions.

Effects on Cellular Growth

Since the initial description of the inhibition of tumor growth in experimental animals by Goerner (27) in 1930, many studies have elucidated the mechanisms of anticancer activity of heparin, Heparin, affects the action of several enzymes by promoting or, more often, by inhibiting their activities. (26) The interaction with growth factors and structural proteins in the extracellular matrix may also be responsible for the potential anticancer effect of heparin. (26)

Heparin (a heterogeneous mixture of molecules of various size) may adhere to various cell types (platelets, endothelial cells, smooth-muscle cells) and in terfere with their behavior. (26) Heparin has been shown to bind basic fibroblast growth factor and hepatocyte G factor/scatter factor, thus inhibiting their potential binding to target cells. (28,29)

Another possible mechanism of anticancer activity of heparin is represented by its ability to alter the expression of oncogenes. An in vitro study (30) showed that heparin suppresses the activation of the mitogen-activated protein kinases (extracellular-signal-regulated kinase family), resulting in a partial suppression of the ability of quiescent cells to enter the cell cycle and induce the c-fos expression. In another in vitro study (31) on renal mesangial cells and vascular smooth-muscle cells, heparin induced a significant suppression of [3H]-thymidine incorporation into DNA in the S-phase, and a decrease and delay in the entry into S/G2 after release of cells from quiescence by serum stimulation.

Heparin induces apoptosis in both human peripheral blood neutrophils and teratocarcinoma cell lines. (32,33) It has been hypothesized that a possible target enzyme for this action of heparin could be a 24-kD enzyme responsible for DNA fragmentation. (34) The observation that multidrug resistance of some cancers can be suppressed by adding heparin to the chemotherapy regimen could be explained by the interference on DNA synthesis and expression of the substance. (35)

Effects on Blood Coagulation Pathway and Platelet Aggregation