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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

Heparin inhibits thrombin through the activation of antithrombin. Thrombin is thought to preserve the integrity of the tumor mass and to promote the tumor cell growth. (26) Heparin would interfere with the mechanism of tumor cell invasion into the extracellular matrix mediated by the urokinase-type plasminogen activator. (26)

As stated above, the process of metastatic colonization involves several steps. Apart from the components of the blood-dotting pathway, other mechanisms are thought to contribute to the metastatic spread by trapping and facilitating the adherence of tumor cells to the capillary walls. (24) In vitro studies (36,37) suggested a role for platelets in the process of hematogenous metastasis. Once invasion of matrix and basement membrane has occurred, tumor cells access the bloodstream. Circulating free tumor cells are efficiently cleared by the host defenses; however, malignant cells may form "microemboli" with platelets and, to a lesser extent, with leukocytes and other host cells, thus evading the host defenses and rendering easier the colonization of distant organs. (38,39) A reduction in platelet count is associated with a reduction of the metastatic potential of a tumor. (40) An early experimental study (41) demonstrated that neuraminidase-induced thrombocytopenia greatly reduces the metastatic process, and that the reduction in platelet counts inhibits metastasis in several experimental tumor systems. However, the specific mechanism by which platelets and endothelial cells participate in the metastatic process is unknown. (42) Two double-blind clinical studies (43,44) showed a slight but significant improvement in survival of patients with NSCLC receiving mopidamole, an analog of dipyridamole that inhibits platelet aggregation.

More recent studies (45,46) indicate that several anionic molecules that inhibit heparanases can diminish the extent of lung colonization by tumor cells. Furthermore, other reports (47,48) showed that carcinoma progression is associated with alterations of the cell surface glycosylation. Of note, carcinomas expressing highly sialylated or branched sugar chains and/or large amounts of mucins have a poor prognosis because of a high rate of metastasis. In particular, the expression of sialylated fucosylated glycans like sialyl Lewis x-a correlates with a poor prognosis because of rapid tumor progression and metastatic spreads Carcinoma cell-surface mucins carrying sialyl Lewis x-a can be ligand for three members of the selectin family of cell adhesion molecules. (49) The selectins can mediate tumor cell interactions with platelets, leukocytes, and endothelium both in vitro and in vivo, (49) this suggesting a role for selectins in the metastatic spread of tumors. Since tumor cell/ platelet complexes promote metastatic spread, P-selectin seemed a logical candidate to mediate the pathologic interactions involving carcinoma cells with platelets, leukocytes, and endothelium. Heparin is an excellent inhibitor of P-selectin binding to its natural ligands, presumably by mimicking these ligands, which contain negatively charged sialyic acids and tyrosine sulfate residues. (25)

Borsig et al (42) demonstrated an early action of heparin on metastasis, which occurs in the vasculature, before tumor cell extravasation into the target organ. In fact, heparin can block P-selectin-based platelet interactions with tumor cell surface mucins and thereby attenuate the metastatic process. (42) In vitro experiments demonstrated that heparin blocks P-selectin-mediated interaction of endogenous platelets with sialylated fucosylated mucins on circulating carcinoma cells, and that this reduces tumor survival. (42)

Although heparin is known to inhibit P-selectin, the are no experimental models showing all the steps of the possible mechanism by which the substance prevents the formation of metastasis via this pathway. As a matter of fact, however, a single heparin dose transiently blocks the initial platelet-tumor ceils interaction and prevents long-term organ colonization. (42) Using another animal model of lung metastasis from melanoma, two LMWHs were found to be highly effective in decreasing the number of lung metastasis on day 21 when administered once subcutaneously, 10 min before IV injection of melanoma cells, or twice a week for 3 weeks. (50) A single administration of both LMWHs did not significantly prolong survival when administered prior to injection of the tumor cells, whereas repeated treatment schedules were found to significantly prolong survival. (50) The increase in survival correlated with the length of LMWH administration. (50)

EXPERIENCE FROM OTHER STUDIES EMPLOYING HEPARIN FOR DIFFERENT PURPOSES

Despite this encouraging biochemical rationale, the possible impact of heparin therapy on survival of patients with NSCLC undergoing surgery, has not been satisfactorily investigated. In a review of the literature, only anecdotal reports of NSCLC regression with both UH and LMWH, as well as either retrospective or uncontrolled studies, can be found. (21,51) Only few randomized trials have been carried out, but none involved patients with operable NSCLC. (25)

In 1975, Elias et al (52) showed a 50% response rate to chemotherapy in 14 patients with inoperable lung cancer treated by chemotherapy and heparin, whereas no response was observed among patients treated with chemotherapy alone. In 1982, Halkin et al (53) observed a 42% decrease in mortality among patients with cancer hospitalized for medical indications and receiving random prophylaxis with heparin. More recently, Lebean et al (54) observed a significant improvement both in the response rate to chemotherapy and in the survival of patients with small-cell lung cancer treated with chemotherapy and heparin, as compared to chemotherapy alone.

The majority of the studies evaluating patients with cancer undergoing surgery provided very interesting results about the potential benefit of perioperative heparin therapy. Although an initial retrospective study (55) on patients with colon cancer submitted to surgery failed to find any advantage in patients receiving heparin, another similar study (56) showed a significant reduction of operative mortality and an improved disease-free interval (not reaching significance) in the group of patients with colon cancer receiving heparin. No significant survival difference was observed. More recently, a retrospective analysis (57) of the razoxane trial ill patients with colon cancer showed that heparin thrombophylaxis had a statistically significant survival benefit. With respect to tumor stage, this benefit was more marked in those with stage III disease. (57) Heparin was also found to reduce the occurrence of liver metastasis in patients treated with adjuvant intraportal chemotherapy after colon resection, as compared to urokinase or nothing. (58) A randomized, controlled trial showed that patients with advanced (stage III) colon cancer treated with surgery plus intraportal fluorouracil and heparin infusion had a significant survival advantage as compared to surgery-only control subjects. (59) In the only prospective, randomized, double-blind trial specifically addressed to compare LMWH and UH, yon Tempelhoff et al (60) provided evidence that LMWH more favorably affected the survival of operated patients with pelvic or breast cancer.

RATIONALE FOR THE CHOICE OF LMWHS IN THE SUGGESTED CLINICAL STUDIES

LMWH is being employed more and more in clinical practice when an indication for heparin use exists. As compared to UH, LMWHs have less nonspecific protein binding and thus a better and more consistent bioavailability, a much more convenient dosing schedule, while selectively inhibiting activated factor X (factor Xa). Overall, LMWHs are easier to manage in the clinical setting than UH, at least for indications of VTE. However, it is possible that the "nonspecific protein binding" of UH may actually be necessary for its putative anticancer mechanism that could be "lost" with LMWH. An in vitro study (25) suggested that LMWHs were effective in inhibiting selectins, although to a lesser extent than UH, but this disadvantage should be compensated by the better bioavailability and the more consistent serum levels of LMWHs.

There are many studies about the use of LMWH for different conditions, especially deep venous thrombosis, (61) pulmonary embolism, (62) and unstable angina. (63,64) Although LMWH is generally used for short periods and then treatment is switched to oral anticoagulation, (61) several studies (65) addressing the possible use of LMWH for long periods showed that this practice is simple and is associated with minimal morbidity. As a consequence, LMWHs have become the drug of choice in pregnant women and in those seeking conception and requiring long-term anticoagulation. (66,67) Hemodialysis represents another setting where LMWHs are used for extended periods. (68)

SUGGESTION OF CLINICAL TRIALS IN NSCLC

In spite of a strong rationale in favor to LMWH therapy in patients with NSCLC submitted to surgery, one cannot predictable which subset of patients will benefit more markedly from this therapeutic approach and which is the optimal time frame for this treatment. It is more likely that LMWH could be more effective in NSCLC patients in the initial stages (I-IIIA) than in patients with metastatic tumors at the time of diagnosis, although regression of metastasis of NSCLC after LMWH treatment has been reported. (51)

The supposed optimal time flame in which one could try to prevent the occurrence of metastasis starts from the earliest possible time after the diagnosis of analignancy, continues through the diagnostic and surgical handling of the ease, and stops at least 2 years after surgery. It is possible that the vascular release of tumor cells is facilitated by diagnostic or therapeutic manipulation during the initial management. We suggest that LMWH-recommended prophylactic VTE doses be administered during this interval, potentially preventing the establishment of new metastatic deposits according to the above described mechanisms. Although there is no preclinical study on the optimal time duration of heparin administration, we believe that a 2-year period would be reasonable due to the fact that NSCLC relapses after surgery occur in almost all the cases within 3 years from surgery, most of them occurring before the end of the second year. (69) Minimal or occult residual disease after surgery is a frequent feature in NSCLC. (70) It has been shown to occur even in pathologically staged I-II tumors, if particular techniques (eg, immunohistochemical examination of bone marrow biopsy or lymph node samples) are employed. (70) LMWII therapy could be effective in the prevention of disease recurrence originating from these loci of residual disease, allowing the host immune response or the apoptotic processes to definitively control the disease.

A study protocol of LMWH in NSCLC should involve patients with every operable stage excluding pIA, whose prognosis is satisfactory. Patients with stage IIIA disease should be offered enrollment either in such a trial with LMWH or in an induction treatment trial with chemotherapy or chemoradiotherapy. The current knowledge about the use of LMWH in patients with cancer undergoing surgery is such that a phase III trial can be proposed. We would randomize patients to either receive LMWH or to be strictly followed up without any adjuvant treatment.

The use of a control study arm treated with placebo seems, in fact, unethical, as it would oblige patients to an invasive administration of placebo for a very long period and with presumably no benefit.

The primary end point of the study we are proposing would be the occurrence of locoregional and distant metastatic spread (disease-free interval) in patients with resected NSCLC. Secondary end points would be the overall survival and the occurrence of VTE.

Such a study should take into account the possible toxicity of heparin derivatives, mainly thrombocytopenia. Therefore, we would exclude patients with history of heparin-induced thrombocytopenia as well as those with hemostasis disorders, active bleeding in the previous weeks, and diseases with possible hemorrhagic complications (peptic ulcer, retinopathies, hemorrhagic cerebrovascular accidents in the last 6 mouths, cerebral aneurysm, and uncontrolled systemic hypertension). Concurrent therapy with oral anticoagulants or platelet antiaggregants should not be considered as an absolute exclusion criterion. The possibility of replacing the oral anticoagulant with an LMWH should be considered.

We think that complications should occur rarely. Apart from thrombocytopenia, adverse effects such as bleeding, osteoporosis, and hepatic or renal impairment are exceptional at prophylactic doses of LMWH, even for long periods of time. Side effects should have a very low incidence, and therapy-related deaths should be rare. It must be considered that adjuvant or neoadjuvant treatment of lung cancer usually carry a significant morbidity and a non-negligible mortality. Thus, the expected morbidity and mortality rate of LMWH administration would be probably largely justified by the possible outcome advantages. To conclude, we believe that sufficient data are presently available in the literature about the possible role and safety of LMWH, so that its thorough evaluation in patients with operable NSCLC can be suggested.

* From the Units of Thoracic Surgery (Dr. Alifano), Medical Ontology (Dr. Benedetti), and Thoracic Endoscopy (Dr. Trisolini), Maggiore-Bellaria Hospital, Bologna, Italy.

REFERENCES

(1) Alberg AJ, Samet JM. Epidemiology of lung cancer. Chest 2003; 123:21S-49S

(2) Samet JM. The epidemiology of lung cancer, Chest 1993; 103:20S-25S

(3) Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest 1997; 111:1710-1717

(4) Porrello C, Alifano M, Forti Parri SN, et al. Surgical treatment of stage I lung cancer: results and prognostic factors. J Cardiovasc Surg 2002; 43:723-727.

(5) Williams DE, Pairolern PC, Davis CS, et al. Survival of patients surgically treated for stage I lung cancer. J Thorac Cardiovasc Surg 1981; 82:70-76

(6) Deslauriers J, Gregoire J. Surgical therapy of early non-small cell lung cancer. Chest 2000; 117:104S-109S

(7) Magdeleinat P, Alifano M, Benbrahem C, et al. Surgical treatment of lung cancer invading the chest wall: results and prognostic factors. Ann Thorac Surg 2001; 71:1094-1099

(8) Alifano M, D'Aiuto M, Magdeleinat P, et al. Surgical treatment of superior sulcus tumor: results and prognostic factors. Chest 2003; 124:996-1003

(9) Regnard JF, Magdeleinat P, Azoulay D, et al. Results of resection for bronchogenic carcinoma with mediastinal lymph node metastases in selected patients. Eur J Cardiothorac Surg 1991; 5:583-586

(10) Osaki T, Sugio K, Hanagirl T, et al. Survival and prognostic factors of surgically resected T4 non-small cell lung cancer. Ann Thorac Surg 2003; 75:1745-1751

(11) Grunenwald DH. Surgery for locally advanced non-small cell lung cancer. Semin Surg Oncol 2003; 21:85-90

(12) Robinson LA, Wagner H Jr, Ruckdeshel JC. Treatment of stage IIIA non-small cell lung cancer. Chest 2003; 123:202S-220S

(13) PORT Metaanalysis Trialists Group. Postoperative radiotherapy in non-small-cell lung cancer: systematic review and metaanalysis of individual patient data from nine randomized controlled trials. Lancet 1998; 352:257-263

(14) Scagliotti GV, Fossati R, Torri V, et al. Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell lung calmer. J Natl Cancer Inst 2003; 95:1453-1461

(15) Le Chevalier Th, on behalf of the IALT Investigators. Results of the Randomized International Adjuvant Lung Cancer Trial (IALT): cisplatin-based chemotherapy (CT) vs no CT in 1867 patients with resected non-small cell lung cancer (NSCLC). [abstract]. Proceedings of the American Society of Clinical Oncology 2003, Abstract no. 6

(16) Rosell R, Gomez-Codina J, Camps c, et at. A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer. N Engl J Med 1994; 330:153-158

(17) Both JA, Fossella F, Komaki R, et al. A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer. J Natl Cancer Inst 1994; 86:673-680

(18) Depierre A, Milleron B, Moro-Sibilot D, et al. Preoperative chemotherapy followed by surgery compared with primary surgery in resectable stage I (except T1N0), II, and IIIa non-small-cell lung cancer. J Clin Oncol 2002; 20:247-253

(19) Herbst RS, Giaceone G, Schiller JH, et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial-INTACT 2. J Clin Oncol 2004; 22:759-761

(20) Stenbygaard LE, Sorensen JB, Olsen JE. Metastatic pattern in adenocarcinoma of the lung: an autopsy study from a cohort of 137 consecutive patients with complete resection. J Thorac Cardiovasc Surg 1995; 110:1130-1135

(21) Park JH, Shim YM, Back HJ, et al. Postoperative adjuvant therapy for stage II non-small cell lung cancer. Ann Thorac Surg 1999; 68:1821-1826

(22) Gould PM, Bonner JA, Sawyer TE, et al. Patterns of failure and overall survival in patients with completely resected T3N0 non-small cell lung cancer. Int J Radial Oncol Biol Phys 1999; 45:91-95

(23) Ichinose Y, Kate H, Koike T, et al. Overall survival and local recurrence of 406 completely resected stage IIIA-N2 non-small cell lung cancer patients: questionnaire survey of the Japan Clinical Ontology Group to plan for a clinical trial. Lung Cancer 2001; 34:29-36

(24) Hejna M, Raderer M, Zielinski CC. Inhibition of metastases by anticoagulants. J Natl Cancer Inst 1999; 91:22-36

(25) Varki NM, Varki AV. Heparin inhibition of selectin-mediated interactions during the hematogenous phase of carcinoma metastasis: rationale for clinical studies in humans. Semin Thromb Haemost 2002; 28:53-66

(26) Cosgrove RH, Zacharski LR, Racine E, et al. Improved cancer mortality with low-molecular-weigh heparin treatment: a review of the evidence. Semin Thromb Haemost 2002; 28:79-87

(27) Goerner A. The influence of anticlotting agents on transplantation and growth of tumor tissue. J Lab Clin Med 1930; 16:369-372

(28) Vlodavsky I, Mohsen M, Lider O, et al. Inhibition of tumor metastasis by heparnase inhibiting species by heparin. Invasion Metastasis 1994; 14:290-302

(29) Parish CR, Coombe DB., Jakobsen KB, et al. Evidence that sulphated polysaccharides inhibit tumor metastasis by blocking tumor-cell-derived heparanases. Int J Cancer 1987; 40: 511-518

(30) Miralem T, Templeton DM. Heparin inhibits Ca2+/calmodulin-dependent kinase II activation and c-fos induction in mesangial cells. Biochem J 1998; 330:651-657

(31) Wang A, Templeton DM. Inhibition of mitogenesis and c-fos induction in mesangial cells by heparin and heparin sulfates. Kidney Int 1996; 49:437-438

(32) Manaster J, Chezar J, Shurtz-Swirski R, et al. Heparin induced apoptosis in human peripheral blood neutrophils. Br J Haematol 1996; 94:48-52

(33) Granerus M, Engstrom W. Growth factors and apoptosis. Cell Prolif 1996; 29:309-314

(34) Wright SC, Wet QS, Zhong J, et al. Purification of a 24-kD protease from apoptotic tumor cells that activates DNA fragmentation. J Exp Med 1994; 180:2113-2123

(35) Maia RC, Wagner K, Cabral BH, et al. Heparin rhodamine 123 extrusion by multidrug resistant cells, Cromer Lett 1996; 106:101-108

(36) Honn KV, Tang DG, Chen YQ. Platelets and cancer metastasis: more than an epiphenomenon, Semin Thromb Haemost 1992; 18:392-415

(37) Honn KV, Tang DG, Crissman JD. Platelets and cancer metastasis: a causal relationship? Cancer Metastasis Rev 1992; 11:325-351

(38) Tanaka NG, Tohgo A, Ogawa H. Platelet aggregating activities of metastatizing tumor cells: V. In situ roles of platelets in hematogenous metastases. Invasion Metastasis 1986; 6:209-224

(39) Nieswandt B, Hafner M, Echtenacher B, et at. Lysis of tumor cells by natural killer cells in mice is impeded by platelets. Cancer Res 1999; 59:1295-1300

(40) Gasic GJ, Gasic TB, Stewart CC. Antimetastatic effects associated with platelet reduction. Proc Nail Acad Sci U S A 1968; 61:46-52

(41) Gasic GJ. Role of plasma, platelets, and endothelial cells in tumor metastasis. Cancer Metastasis Rev 1984; 3:99-114

(42) Borsig L, Wong R, Feramisco J. Heparin and cancer revisited: mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis. Proc Natl Acad Sci U S A 2001; 98:3352-3357

(43) Zacharski LR, Moritz TE, Baczek LA, et al. Effect of mopidamole on survival in carcinoma of the lungs and colon: final report of VA cooperative study n. 188. J Natl Cancer Inst 1988; 80:90-97

(44) Schneider B, Geser C, Feurer W. El}bet on anticoagulation treatment with RA-233 (mopidamole) on survival in bronchial cancer. Thromb Haemost 1987; 58:508-512

(45) Miao HQ, Elkin M, Aingorn E, et al. Inhibition of heparanase activity and tumor metastasis by laminarin sulfate and synthetic phosphorothioate oligodeoxynucleotides. Int J Cancer 1999; 83:424-431

(46) Parish CR, Freeman G, Brown KJ. Identification of sulfated oligosaccharide-based inhibitors of ironer growth and metastasis using novel in vitro assay for angiogenesis and heparanase activity, Cancer Res 1999; 59:3433-3441

(47) Dennis JW, Laferte S. Tumor cell surface carbohydrate and the metastatic phenotype. Cancer Metastasis Rev 1987; 5:185-294

(48) Kiln YJ, Varki A. Perspectives on the significance of altered glycosylation of glycoproteins in cancer. Glycoconj J 1997; 14:569-576

(49) Mannori G, Crottet C, Cecconi O. Differential colon cancer cell adhesion to E-, P-, and L-selectin: role of mucin-type glycoproteins. Cancer Res 1995; 55:4425-4431

(50) Sciumbata T, Calcite P, Pimvano P, et al. Treatment with modified heparins inhibits experimental metastasis formation and leads, in some animals, to king term survival. Invasion Metastasis 1996; 16:132-143

(51) Loynes JT, Zacharski LR. Rigas JR. Regression of metastatic non-small cell lung cancer with low molecular weigh heparin. Thromb Haemost 2002; 88:686

(52) Elias E, Shulka S, Mink I, Heparin and chemotherapy in the management of inoperable lung cancer. Cancer 1975; 36: 129-136

(53) Halkin H, Goldberg J, Modan M, et al. Reduction of mortality in general medicine patients by low dose heparin prophylaxis. Ann Int Med 1982; 96:561-565

(54) Lebeau B, Chastang C, Brechot JM, et al. Subcutaneous heparin treatment increases survival in small cell lung cancer. "Petites Cellules" Group. Cancel 1994; 74:38-45

(55) Torngren S, Rieger A. The influence of heparin and curable resection on the survival of colorectal cancer. Acta Chir Stand 1983; 149:427-429

(56) Kohanna FH, Sweeney J, Hussey S, et al. Effect of pert operative low-dose heparin administration on the course of colon cancer. Surgery 198& 93:433-438

(57) Kingston B, Fielding LD, Palmer M. Pert-operative heparin a possible adjuvant to surgery in colorectal cancer? Int J Colorectal Dis 1993; 8:11-15

(58) Wereldsma J, Bruggink E, Meijer W, et at. Adjuvant portal liver infusion in colorectal cancer with fluorouracil/heparin versus urokinase versus control. Cancer 1999; 65:425-432

(59) Fielding LP, Hittinger R, Grace RH, et al. Randomised controlled trial of adjuvant chemotherapy by portal-vein perfusion after curative resection for colorectal adenocarcinoma. Lancet 1992; 340:502-506

(60) von Tempelhoff GF, Harenberg J, Niemann F, et al, Effect of low-molecular weight heparin (certoparin) versus unfractionated heparin on cancer survival following breast and pelvic cancer surgery: a prospective randomized double blind trial. Int J Oncol 2000; 16:815-824

(61) Hirsh J, Lee AY. How we diagnose and treat deep vein thrombosis. Blood 2002; 99:3102-3110

(62) Hull BD, Raskob GE, Brant BF, et el. Low-molecular-weight heparin versus heparin in the treatment of patients with pulmonary embolism: American Canadian Thrombosis Study Group. Arch Intern Med 2000; 24:229-236

(63) Verheugt FW. Low-molecular-weight heparin and other antithrombotic agents in the setting of a primarily medical treatment of unstable coronary artery, disease. Haemostasis 2000; 30:1228-1278

(64) Borja J. Role of low-molecular-weight heparin in the management of acute coronary syndromes. Curr Opin Cardiol 2002; 17:608-612

(65) Monreal M. Long term treatment of venous VTE with low-molecular weight hepmin. Curr Opin Pulm Med 2000; 6:326-329

(66) Greer IA. The acute management of VTE in pregnancy. Curr Opin Obstet Cynecol 2001; 13:569-575

(67) Greer IA. Exploring the role of low-molecular-weight heparins in pregnancy. Semin Thromb Haemost 2002; 28:25S-31S

(68) Stefoni S, Cianciolo G, Donati C, et al. Standard heparin versus low-molecular-weight heparin: a medium-term comparison in hemodialysis. Nephron 2002; 92:589-600

(69) Colice GL, Rubins J, Unger M. Follow-up and surveillance of the lung cancer patient following curative-intent therapy. Chest 2003; 123:272S-283S

(70) Hosch SB, Scheunemann P, Izbicki JR. Minimal residual disease in non-small cell lung cancer. Semin Surg Oncol 2001; 20:278-281

Manuscript received November 18, 2003; revision accepted March 23, 2004.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: permissions@chestnet.org).

Correspondence to: Marco Alifano, MD, Chirurgia Toracica, Ospedale Maggiore, Largo B. Nigrisoli 2, 40100 Bologna, Italy. e-mail: marcoalifano@yahoo.com

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