SEARCH

SEARCH BY CITATION

Keywords:

  • chemotherapy;
  • dalteparin;
  • low-molecular-weight heparin;
  • small cell lung cancer

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Patients
  6. Pretreatment evaluation
  7. Treatment regimen
  8. Statistical analyses
  9. Results
  10. Patients characteristics
  11. Response to chemotherapy
  12. Survival
  13. Toxicity
  14. Discussion
  15. Acknowledgements
  16. References

Summary. Background Small cell lung cancer (SCLC) is a chemotherapy-responsive tumor type but most patients ultimately experience disease progression. SCLC is associated with alterations in the coagulation system. The present randomized clinical trial (RCT) was designed to determine whether addition of low-molecular-weight heparin (LMWH) to combination chemotherapy (CT) would improve SCLC outcome compared with CT alone. Methods Combination CT consisted of cyclophosphamide, epirubicine and vincristine (CEV) given at 3-weekly intervals for six cycles. Eighty-four patients were randomized to receive either CT alone (n = 42) or CT plus LMWH (n = 42). LMWH consisted of dalteparin given at a dose of 5000 U once daily during the 18 weeks of CT. Results Overall tumor response rates were 42.5% with CT alone and 69.2% with CT plus LMWH (P = 0.07). Median progression-free survival was 6.0 months with CT alone and 10.0 months with CT plus LMWH (P = 0.01). Median overall survival was 8.0 months with CT alone and 13.0 months with CT plus LMWH (P = 0.01). Similar improvement in survival with LMWH treatment occurred in patients with both limited and extensive disease stages. The risk of death in the CT + LMWH group relative to that in the CT group was 0.56 (95% confidence interval 0.30, 0.86) (P = 0.012 by log rank test). Toxicity from the experimental treatment was minimal and there were no treatment-related deaths. Conclusions These results support the concept that anticoagulants, and particularly LMWH, may improve clinical outcomes in SCLC. Further clinical trials of this relatively non-toxic treatment approach are indicated.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Patients
  6. Pretreatment evaluation
  7. Treatment regimen
  8. Statistical analyses
  9. Results
  10. Patients characteristics
  11. Response to chemotherapy
  12. Survival
  13. Toxicity
  14. Discussion
  15. Acknowledgements
  16. References

Lung cancer is a major tumor type worldwide. Small cell lung cancer (SCLC) differs from other histopathological types of lung cancer because of its rapid clinical progression, and its relative sensitivity to chemotherapy (CT) and radiotherapy (RT) [1]. Activation of the coagulation system occurs commonly in patients with malignancy [2–5]. SCLC in particular is characterized by tumor cell thrombin generation and local fibrin formation that may contribute to the growth of this tumor type [5,>6]. Several studies have suggested that anticoagulant therapy may improve survival in patients with SCLC [7]. Specifically, improved SCLC disease outcome has been observed in randomized clinical trials (RCTs) of warfarin [8,>9] and unfractionated heparin [10], and in a Phase II study of urokinase [11]. However, further clinical studies are needed to define the role that anticoagulants will play, if any, in the treatment of SCLC and other tumor types. The low-molecular-weight heparins (LMWHs) lend themselves to such studies because of their effects in experimental models of malignancy [12] and the relative ease of administration compared with unfractionated heparin [13]. The purpose of the present RCT was to determine whether addition of LMWH to CT would improve SCLC patient outcome compared with CT alone.

Patients

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Patients
  6. Pretreatment evaluation
  7. Treatment regimen
  8. Statistical analyses
  9. Results
  10. Patients characteristics
  11. Response to chemotherapy
  12. Survival
  13. Toxicity
  14. Discussion
  15. Acknowledgements
  16. References

Patients between ages 18 and 75 years with histologically confirmed SCLC were entered provided they had Eastern Cooperative Oncology Group (ECOG) performance status (PS) of less than 3 and normal hematological, renal and hepatic function tests (absolute neutrophil count ≥ 1500 mL−1, platelets ≥ 150 000 mL−1, creatinine 0.6–1.2 mg dL−1, total bilirubin ≤ 3 mg dL−1, AST ≤ 35 U L−1, ALT ≤ 45 U L−1). Patients were excluded if they had another medical illness or a hemorrhagic diathesis, previous or concomitant cancer except basal cell carcinoma of skin and cervical carcinoma in situ, or had received CT or RT previously.

Pretreatment evaluation

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Patients
  6. Pretreatment evaluation
  7. Treatment regimen
  8. Statistical analyses
  9. Results
  10. Patients characteristics
  11. Response to chemotherapy
  12. Survival
  13. Toxicity
  14. Discussion
  15. Acknowledgements
  16. References

All staging, patient monitoring and other follow-up procedures were performed according to standard, widely accepted practices and criteria [1]. The histological diagnosis was typically established by lesion biopsy using fiberoptic bronchoscope or computed tomography (CT)-guided transthoracic lung biopsy. Disease stage was classified as either limited or disseminated using standard criteria [1] based on the clinical examination, routine radiography, CT brain and thoracic scanning, unilateral iliac crest bone marrow aspiration and biopsy, radionuclide bone scanning and abdominal ultrasonography and/or CT. Pretreatment and follow-up radiological studies related to staging and evaluation of response to the treatment were performed in the Radiology Department of our institute which is separate from the clinical treatment area, and the treatment group to which the patients were assigned was not known by the radiologist. Blood tests performed at entry included the complete blood count, electrolytes, creatinine, calcium, alkaline phosphatase and transaminase levels, and prothrombin time. The complete blood count and chemistry analyses were repeated before each course of CT.

Treatment regimen

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Patients
  6. Pretreatment evaluation
  7. Treatment regimen
  8. Statistical analyses
  9. Results
  10. Patients characteristics
  11. Response to chemotherapy
  12. Survival
  13. Toxicity
  14. Discussion
  15. Acknowledgements
  16. References

Patients were randomized to receive either CT or CT plus LMWH. First-line CT consisted of cyclophosphamide 750 mg m−2, epirubicine 90 mg m−2, and vincristine 1 mg m−2 (maximum 2 mg) given intravenously on day 1 of every 3-weekly cycle for six cycles. LMWH (dalteparin), 5000 U once daily, was administered throughout the 18 weeks of chemotherapy. The patients were trained by an oncology nurse and injections were self-administered by the patient using prefilled syringes. The LMWH was stopped with disease progression or at the end of the 18 weeks of chemotherapy. Patients with limited disease at entry received local thoracic RT if a partial response or stable disease was evident after six courses of CT. RT treatment portals with a 2-cm margin around any gross tumor and 1-cm margin around electively treated regional lymph node areas were designed. Patients achieving complete remission also received prophylactic cranial irradiation (10 × 250 cGy, total 2500 cGy).

The side-effects were graded according to the toxicity scale of the National Cancer Institute (NCI) Common Toxicity Criteria. Chemotherapy dose reduction, 25% of prior total dose, was used in patients who had grade 4 myelotoxicity [1].

Statistical analyses

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Patients
  6. Pretreatment evaluation
  7. Treatment regimen
  8. Statistical analyses
  9. Results
  10. Patients characteristics
  11. Response to chemotherapy
  12. Survival
  13. Toxicity
  14. Discussion
  15. Acknowledgements
  16. References

The sample size was designed to provide the study with 80% power at a 0.05 significance level to detect a difference of 0.26 between 26% and 52%—the proportions surviving at 1 year in groups 1 and 2, respectively (hazard ratio 0.49). Eighty-four patients that met the above entry criteria were enrolled into this study. Survival was analyzed on an intent-to-treat basis. Differences between the two groups in terms of age were compared by the Mann–Whitney U-test. The χ2 test was used to compare differences between the two groups for various parameters including sex, stage, smoking history, and performance status. Survival was calculated from the date of diagnosis to the date of first progression (progression-free survival) or death (overall survival). Disease-free and overall survival time and survival rates were estimated using the method of Kaplan–Meier and compared using the log-rank test. Descriptive statistics and survival analysis were performed with SPSS version 10.0 (SPSS Inc, Chicago, IL, USA) and MedCalc 6.16 software package program.

Patients characteristics

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Patients
  6. Pretreatment evaluation
  7. Treatment regimen
  8. Statistical analyses
  9. Results
  10. Patients characteristics
  11. Response to chemotherapy
  12. Survival
  13. Toxicity
  14. Discussion
  15. Acknowledgements
  16. References

Eighty-four previously untreated patients were randomized to this study, 42 patients to each treatment group, between December 1998 and September 2001. The median age was 58 years (range 34–75). Sixty-nine patients were smokers, 57.1% of patients had limited disease and 42.9% extensive disease. Patient characteristics at entry, summarized in Table 1, show the balance between treatment groups. Patients in both groups received median six cycles of chemotherapy. Patients in the CT + LMWH group received a median of 18 weeks of LMWH. Seventeen patients in the CT group and 16 in the CT + LMWH group who had limited stage disease and obtained partial remission or stable disease after six cycles of chemotherapy received thoracic radiotherapy.

Table 1.  Patient characteristics
CharacteristicCT (N = 42)CT + LMWH (N = 42)P-value
  1. LDH, Lactic dehydrogenase; NSE, neuron-specific enolase. *ECOG, Eastern Cooperative Oncology Group.

Age (years)  0.49
 Median 58 57.5 
 Range 37–75 34–74 
Sex  0.57
 Male 3533 
 Female79 
LDH (U L−1)  0.681
 Median434472 
 Range300–2355278–1001 
NSE (ng mL−1)  0.611
 Median45.729.2 
 Range4.9–176.88–209 
Stage  0.65
 Limited disease2523 
 Pleural effusion (+)57 
 Extensive disease1719 
 One metastatic site1315 
 Two metastatic sites44 
Smoking history  0.77
 Smoker3435 
 Non-smoker87 
Performance status (ECOG)*0.74
 053 
 12426 
 21313 

Response to chemotherapy

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Patients
  6. Pretreatment evaluation
  7. Treatment regimen
  8. Statistical analyses
  9. Results
  10. Patients characteristics
  11. Response to chemotherapy
  12. Survival
  13. Toxicity
  14. Discussion
  15. Acknowledgements
  16. References

The response to therapy according to treatment group is summarized in Table 2. Seventy-nine patients were eligible for evaluation of treatment response. An overall objective response occurred in 55.7% of patients, 42.5% with CT alone and 69.2% with CT plus LMWH (P = 0.07). In patients with limited disease, the overall objective response rate was 60.0% with CT alone and 91.4% with CT plus LMWH (P = 0.02). In patients with extensive disease, the overall objective response rate was 13.3% with CT alone and 37.4% with CT plus LMWH (P = 0.59). In case of disease progression or relapse during first-line treatment, cisplatin etoposide combination chemotherapy was administered to 18 patients in the CT group and 14 patients in the CT plus LMWH group.

Table 2.  Response to treatment according to treatment group, N (%)
 CT (N = 40)CT + LMWH (N = 39)
LimitedExtensiveTotalLimitedExtensiveTotal
  1. Chemotherapy (CT) vs. CT + low-molecular-weight heparin (LMWH): P = 0.07 for all patients; P = 0.02 for limited disease patients; P = 0.59 for extensive disease patients.

Complete response1 (4.0)0 (0.0)1 (2.5)6 (26.1)1 (6.2)7 (17.9)
Partial response14 (56.0)2 (13.3)16 (40.0)15 (65.3)5 (31.2)20 (51.3)
Stable disease3 (12.0)4 (26.7)7 (17.5)1 (4.3)3 (18.8)4 (10.3)
Progressive disease7 (28.0)9 (60.0)16 (40.0)1 (4.3)7 (43.8)8 (20.5)

Survival

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Patients
  6. Pretreatment evaluation
  7. Treatment regimen
  8. Statistical analyses
  9. Results
  10. Patients characteristics
  11. Response to chemotherapy
  12. Survival
  13. Toxicity
  14. Discussion
  15. Acknowledgements
  16. References

During this study, 66 of the 84 patients (76.2%) died of their disease and the remaining 18 patients were alive at the time of this analysis. At a 10-month (range 2–33 months) median follow-up, analysis of survival revealed a significant difference between treatment groups in favor of CT + LMWH. The 1- and 2-year progression-free survival (PFS) rates were 11.7% and 0.0% and the median survival 6.0 ± 0.81 months [95% confidence interval (CI) 4.42, 7.58) for patients treated with CT alone. The 1- and 2-year PFS rates were 30.4% and 3.4% and the median survival 10.0 ± 0.95 months (95% CI 8.14, 11.86) for patients treated with CT + LMWH. These differences between treatment groups were statistically significant (P = 0.01).

The 1- and 2-year overall survival (OS) rates were 29.5% and 0.0%, and the median survival 8.0 ± 0.95 months (95% CI 6.14, 9.86) for patients treated with CT alone. The 1- and 2-year survival rates were 51.3% and 17.2%, and the median survival 13.0 ± 1.62 months (95% CI 9.83, 16.17) for patients treated with CT + LMWH (P = 0.01). The significant difference in PFS and OS favoring patients treated with CT + LMWH was also observed for each stage analyzed separately (P = 0.025 with limited disease and P = 0.012 with extensive disease for PFS; P = 0.007 with limited disease and P = 0.012 with extensive disease for OS). These results are summarized in Table 3 and Figs 1–3. The risk of death in the CT + LMWH group relative to that in CT group was 0.56 (95% CI 0.30, 0.86) (P = 0.012 by log-rank test).

Table 3.  Estimated survival (months) using Kaplan–Meier analysis according to tumor stage
 CT, median ± SD (95% CI)CT + LMWH, median ± SD (95% CI)
LimitedExtensiveLimitedExtensive
  1. Chemotherapy (CT) vs. CT + low-molecular-weight heparin (LMWH): P = 0.025 in limited disease and P = 0.012 in extensive disease for progression-free survival (PFS); P = 0.007 in limited disease and P = 0.012 in extensive disease for overall survival (OS).

PFS8.0 ± 1.21 (5.62–10.38)6.0 ± 0.81 (4.42–7.58)11.0 ± 1.44 (8.17–13.83)10.0 ± 0.95 (8.14–11.86)
OS10.0 ± 1.39 (7.28–12.72)8.0 ± 0.95 (6.14–9.86)16.0 ± 3.91 (8.34–23.66)13.0 ± 1.62 (9.83–16.17)
image

Figure 1. (A) Analysis of progression-free survival (Kaplan–Meier) for all patients [- - -, chemotherapy (CT)-treated patients; —, CT + low-molecular-weight heparin (LMWH)-treated patients; P = 0.01]. (B) Analysis of overall survival (Kaplan–Meier) for all patients (- - -, CT-treated patients; —, CT + LMWH-treated patients; P = 0.01).

Download figure to PowerPoint

image

Figure 2. (A) Analysis of overall survival (Kaplan–Meier) for patients with limited disease [- - -, chemotherapy (CT)-treated patients; —, CT + low-molecular-weight heparin (LMWH)-treated patients; P = 0.007]. (B) Analysis of overall survival (Kaplan–Meier) for patients with extensive disease (- - -, CT-treated patients; —, CT + LMWH-treated patients; P = 0.01).

Download figure to PowerPoint

image

Figure 3. (A) Analysis of progression-free survival (Kaplan–Meier) for patients with limited disease [- - -, chemptherapy (CT)-treated patients; —, CT + low-molecular-weight heparin (LMWH)-treated patients; P = 0.025]. (B) Analysis of progression-free survival (Kaplan–Meier) for patients with extensive disease (- - -, CT-treated patients; —, CT + LMWH-treated patients; P = 0.012).

Download figure to PowerPoint

Toxicity

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Patients
  6. Pretreatment evaluation
  7. Treatment regimen
  8. Statistical analyses
  9. Results
  10. Patients characteristics
  11. Response to chemotherapy
  12. Survival
  13. Toxicity
  14. Discussion
  15. Acknowledgements
  16. References

One patient treated with CT + LMWH had rectal bleeding after the first course of chemotherapy (without changes in blood counts or coagulation test results), which subsided within a week. LMWH was discontinued during this interval but resumed when no lesion was detected on colonoscopy. This bleeding did not recur. The toxicity of the drug combination used was mild and well tolerated. There were no treatment-related deaths. Myelosuppression was mild to moderate. Grade 3–4 neutropenia was detected in five patients (11.9%) in the CT + LMWH group and one patient (2.4%) in the CT-only group. Neutropenia was greater in patients treated with CT + LMWH compared with those treated with CT alone but this difference was not statistically significant (P = 0.09). A febrile episode during neutropenia occurred in one patient in the CT + LMWH group. Grade 2 thrombocytopenia (nadir platelet count 73 000 µL−1) during the neutropenic period was observed in one patient treated with CT + LMWH but the platelet count rose subsequently along with recovery of the neutrophil count and this thrombocytopenia was not thought to be a manifestation of LMWH toxicity.

During the CT treatment period, one patient in the CT group developed a left lower extremity deep vein thrombosis, which was diagnosed clinically and proven radiologically, and treated appropriately with anticoagulant therapy. This patient was included in the overall analysis of outcome. No clinical episodes of thrombosis were observed in the CT + LMWH group.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Patients
  6. Pretreatment evaluation
  7. Treatment regimen
  8. Statistical analyses
  9. Results
  10. Patients characteristics
  11. Response to chemotherapy
  12. Survival
  13. Toxicity
  14. Discussion
  15. Acknowledgements
  16. References

Combination CT is standard treatment for SCLC [1]. The combination of cyclophosphamide, doxorubicin/epirubicin and vincristine is one of the most commonly studied regimens, producing median survival of about 8 months for patients with extensive stage disease and 12 months for patients with limited stage disease. Although progress has been made with modern CT regimens, patient outcomes remain unsatisfactory and new treatment concepts are needed [14]. Coagulation abnormalities that may be exaggerated by CT are known to exist in malignancy in general and SCLC in particular [2–5,15]. The coagulation mechanism and drugs that interrupt this mechanism may modify tumor growth but variable effects of different interventions and possible heterogeneity of responsiveness between tumor types remain to be clarified [7].

Several clinical trials have suggested that SCLC may be particularly susceptible to interventions aimed at the coagulation mechanism. Zacharski et al. showed that addition of warfarin to combination CT produced significantly improved survival in patients with SCLC but not in patients with several other tumor types [8]. Chahinian et al. confirmed the favorable effects of warfarin + CT in a RCT involving 328 patients with extensive stage SCLC [9]. In a RCT performed in 272 patients with SCLC, Lebeau et al. studied effects of alternating combination CT with or without subcutaneous unfractionated heparin (UFH) given for 5 weeks [10]. Patients receiving UFH experienced significantly improved response rates and survival. Favorable effects of UFH were particularly evident in patients with limited stage disease. These same workers showed previously in a RCT that aspirin treatment had no effect on the natural history of SCLC [16]. In a Phase II study, fibrinolytic therapy with urokinase appeared to have a favorable effect on the course of SCLC [11].

Effects of LMWH on the clinical course of SCLC have not been defined previously. LMWH is particularly suited to evaluation in RCTs in cancer because of its ease of administration subcutaneously by self-injection, usually without need for dose monitoring [13]. Several LMWHs are approved throughout the world for the prevention and treatment of deep vein thrombosis, a common complication of cancer, and this class of drugs is well-known to the field of oncology. LMWH would be expected to have superior effects on malignant growth compared with UFH based on studies in experimental tumor models [12].

Our results suggest that doses of the LMWH, dalteparin, that are approved for prevention of deep vein thrombosis may improve significantly the course of SCLC when added to combination CT. Response rates were improved with LMWH, especially in patients with limited disease extent. Importantly, both PFS and OS were significantly improved with addition of LMWH to CT, and this survival advantage was observed in patients with both limited and extensive stage disease. In the CT-only group, we observed median survival of extensive stage patients, which was similar to that reported previously for this particular CT regimen. However, we observed lower median survival in patients with limited stage disease. This is mostly due to delay in administration of radiation therapy according to the study design and it should also be noted that cisplatin-containing regimens are superior to regimens that do not include cisplatin in limited disease patients, but not in extensive disease patients [17]. Toxicity from the experimental (LMWH) therapy in the present study was minimal. One patient experienced rectal bleeding shortly after starting LMWH in the absence of an identifiable colonic lesion. However, this bleeding subsided and the LMWH was resumed without further bleeding.

The LMWHs are members of a larger family of compounds known as glycosaminoglycans that are capable of modifying tumor growth by several possible mechanisms. These include inhibition of tumor growth factors, angiogenesis, heparinase, and thrombin generation as well as reversal of multidrug resistance and other possible mechanisms [12, 18]. Inhibition of angiogenesis may be mediated by heparin-induced release of the antiangiogenic peptide, tissue factor pathway inhibitor, from the vascular endothelium [19]. While the mechanism of action of LMWH in SCLC is as yet undefined, tumor cells in this malignancy are known to express a thrombin-generating pathway in situ with local fibrin formation [6]. Further studies should clarify the mechanism of action of LMWH in SCLC as well as other tumor types. Kakkar et al. recently reported the results of the FAMOUS trial that was specifically designed to test the effect of LMWH on survival in patients with cancer. In this trial 385 patients with advanced solid tumors were randomized to receive either the LMWH, dalteparin, or placebo for up to 1 year. No difference was detected in survival at 1 year. However, in a subgroup analysis of good prognosis patients, there was a statistically significant improvement in survival in favor of the LMWH [20].

Our results confirm and extend previous results showing favorable effects of warfarin and UFH on the clinical course of SCLC. A limitation of our study is that the LMWH was given only for the duration of the CT. It is not known whether more prolonged therapy or the use of other LMWHs with differing properties would yield different results. It is possible that several components of the blood coagulation mechanism may contribute to tumor growth [9]. Evaluation of interventions aimed at intercepting such growth control pathways relevant to individual tumor types may be worthy of further consideration for the experimental treatment of human malignancy. The long-term good results of this trial have led us to begin a new study to test the efficacy of extending the duration of LMWH administration for up to 1 year. In this study, combination CT will include cisplatin in limited and extensive stage patients and early combination chemo–radiotherapy in limited stage patients.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Patients
  6. Pretreatment evaluation
  7. Treatment regimen
  8. Statistical analyses
  9. Results
  10. Patients characteristics
  11. Response to chemotherapy
  12. Survival
  13. Toxicity
  14. Discussion
  15. Acknowledgements
  16. References
  • 1
    Murren J, Glatstein E, Pass HI. Small cell lung cancer. In: DeVitaVT, HellmanS, RosenbergSA, eds. Cancer Principles and Practice of Oncology, 6th edn. Philadelphia: Lippincott Williams & Wilkins, 2001: 9831018.
  • 2
    Naschitz J, Yeshurun D, Lev LM. Thromboembolism in cancer. Cancer 1993; 71: 138490.
  • 3
    Van Wersch JW, Tjwa MK. Coagulation/fibrinolysis balance and lung cancer. Haemostasis 1991; 21: 11723.
  • 4
    Glassman AB, Jones E. Thrombosis and coagulation abnormalities associated with cancer. Ann Clin Lab Sci 1994; 24: 15.
  • 5
    Wojtukiewicz MZ, Zacharski LR, Memoli VA, Kisiel W, Kudryk BJ, Rousseau SM, Stump DC. Abnormal regulation of coagulation/fibrinolysis in small cell carcinoma of the lung. Cancer 1990; 65: 4815.
  • 6
    Zacharski LR, Memoli VA, Morain WD, Schlaeppi J-M, Rousseau SM. Cellular localization of enzymatically active thrombin in intact human tissue by hirudin binding. Thromb Haemost 1995; 73: 7937.
  • 7
    Zacharski LR. Anticoagulants in cancer treatment: malignancy as a solid phase coagulopathy. Cancer Lett 2002; 186: 19.
  • 8
    Zacharski LR, Henderson WG, Rickles FR, Forman WB, Cornell CJ Jr, Forcier RJ, Edwards RL, Headley E, Kim SH, O'Donnell JF, O'Dell R, Tornyos K, Kwaan HC. Effect of warfarin anticoagulation on survival in carcinoma of the lung, colon, head and neck, and prostate. Final report of VA cooperative study #75. Cancer 1984; 53: 204652.
  • 9
    Chahinian AP, Propert KJ, Ware JH, Zimmer B, Perrymc C, Hirsh V, Skarin A, Kopel S, Holland JF, Comis RL. A randomized trial of anticoagulation with warfarin and of alternating chemotherapy in extensive small-cell lung cancer by the Cancer and Leukemia Group B. J Clin Oncol 1989; 7: 9931002.
  • 10
    Lebeau B, Chastang C, Brechot JM, Capron F, Dautzenberg B, Delaisements C, Mornet M, Brun J, Hurdebourcq JP, Lemaire E. Subcutaneous heparin treatment increases survival in small cell lung cancer. Cancer 1994; 74: 3845.
  • 11
    Calvo FA, Hidalgo OF, Gonzales F, Rebollo J, Martin Algarra S, Ortiz de Urbina D, Brugarolas A. Urokinase combination chemotherapy in small cell lung cancer. Cancer 1992; 70: 262430.
  • 12
    Zacharski LR, Ornstein DL. Heparin and cancer. Thromb Haemost 1998; 80: 1023.
  • 13
    Weitz JL. Low molecular weight heparin. N Engl J Med 1997; 337: 68898.
  • 14
    Bunn PA, Carney DN. Overview of chemotherapy for small cell lung cancer. Semin Oncol 1997; 24: S769–S7-74.
  • 15
    Gabazza EC, Taguchi O, Yamakami T, Machishi M, Ibata H, Suzuki S, Shima T. Alteration of coagulation and fibrinolysis systems after multidrug anticancer therapy for lung cancer. Eur J Cancer 1994; 30A: 127681.
  • 16
    Lebeau B, Chastang C, Muir F, Vincent J, Massin F, Fabre C. No effect of an antiaggregant treatmant with aspirin in small cell lung cancer treated with CCAVP16 chemotherapy. Cancer 1993; 71: 17415.
  • 17
    Sandler AB. Chemotherapy for small cell lung cancer. Semin Oncol 2003; 30: 925.
  • 18
    Maria RC, Wagner K, Cabral RH, Rumjanek VM. Heparin rhadamine 123 extrusion by multidrug resistant cells. Cancer Lett 1996; 106: 1018.
  • 19
    Mousa SA. Anticoagulants in thrombosis and cancer: the missing link. Sem Thromb Hemost 2002; 28: 4552.
  • 20
    Kakkar AK, Kadziola Z, Willamson RCN, Levine MN, Low V, Lemoine NR. Low molecular weight heparin therapy and survival in advanced cancer. Blood 2002; 100: 557 (Abstract).