|LUNG CANCER SYMPOSIUM: ORIGINAL ARTICLE
|Year : 2014 | Volume
| Issue : 3 | Page : 324-329
The effect of small-molecular-weight heparin added to chemotherapy on survival in small-cell lung cancer - A retrospective analysis
M Altinbas1, M Dikilitas2, M Ozkan2, GG Dogu3, O Er4, HS Coskun5
1 Diskapi Yildirim Beyazit Education and Research Hospital, Ankara, Turkey
2 Erciyes University Medical Faculty, Department of Medical Oncology, Kayseri, Turkey
3 Denizli University Medical Fakulty, Department of Medical Oncology, Denizli, Turkey
4 Acibadem University, Maslak Hospital Department of Medical Oncology, Istanbul, Turkey
5 Akdeniz University Medical Faculty, Department of Medical Oncology, Antalya, Turkey
|Date of Web Publication||10-Dec-2014|
Diskapi Yildirim Beyazit Education and Research Hospital, Ankara
Source of Support: None, Conflict of Interest: None
Aims and Background: Small cell lung cancer (SCLC) is a chemotherapy-responsive tumor and associated with alterations in the coagulation system. Addition of low-molecular-weight heparin (LMWH) to combination chemotherapy (CT) had resulted in increase in survival. The present retrospective trial was designed to determine whether the duration of dalteparin usage has an effect on progression and survival. Materials and Methods: The medical records of 67 patients with SCLC who were given cisplatin-etoposide and concomitant LMWH (dalteparin) was evaluated retrospectively. Results: Median follow-up of patients was 11.3 months. Outcome: 10.6% complete response, 3.0% good partial response, 36.4% partial response, 10.6% stable disease, and 39.4% progressive disease. Side-effects were seen in 40.3% of the patients. Median dalteparin duration was 6,1 months. According the duration of dalteparin patients were grouped in three: who took dalteparin less than 4 months (Group A), 4-6 months (Group B) and more than 6 months (Group C). Mean overall survival (OS) in Group A was 6.5 months, in Group B 11.8 months, and Group C 14.6 months. Mean OS in Group B and C were statistically significantly (P < 0.001) longer than Group A, between Group B and C there was not any significant difference (P = 0.037). Mean progression free survival (PFS) was 9 months. Conclusions: The CT plus LMWH minimum 4 months long is well-tolerable, and may improve PFS and OS in patients with SCLC. For treatment of patients with SCLC CT plus LMWH may be considered as effective future-therapy, and further multi-centre randomised prospective clinical trials must be done to determine the new standard treatment approach for SCLC.
Keywords: Chemotherapy, dalteparin, low-molecular-weight heparin, small cell lung cancer, survival
|How to cite this article:|
Altinbas M, Dikilitas M, Ozkan M, Dogu G G, Er O, Coskun H S. The effect of small-molecular-weight heparin added to chemotherapy on survival in small-cell lung cancer - A retrospective analysis. Indian J Cancer 2014;51:324-9
|How to cite this URL:|
Altinbas M, Dikilitas M, Ozkan M, Dogu G G, Er O, Coskun H S. The effect of small-molecular-weight heparin added to chemotherapy on survival in small-cell lung cancer - A retrospective analysis. Indian J Cancer [serial online] 2014 [cited 2020 Feb 25];51:324-9. Available from: http://www.indianjcancer.com/text.asp?2014/51/3/324/146784
| » Introduction|| |
Lung cancer is one of the most common cancers in the world. Small-cell lung cancer (SCLC) is different from other histopathological types with regards to different biological behavior, good response to chemotherapy and rapid hematogeneous spreading.  Like other cancers, SCLC is also associated with hypercoagulability. Low-molecular-weight heparin (LMWH) maximizes the systemic therapeutic response of the tumor by dissolving the thrombus plug and makes circulating tumor cells subject to the chemotherapy by dissolving the tumorous tissue into the blood.  Previous studies showed that anticoagulant therapy increases the survival rates in SCLC. ,, LMWH is easier to use than warfarin and fractioned heparin, also has less potential side effects. ,, A previous study showed that usage of LMWH in both limited and extended stage SCLC increases both PFS and OS, compared with the group that did not take dalteparin.  This study was designed to show whether the duration of dalteparin usage affects the progression and survival.
| » Materials and Methods|| |
We evaluated retrospectively the 67 of 68 patients to whom dalteparin was prescribed combined with the chemotherapy in our department between the years 2001-2005. One patient was excluded from the study because of lack of information in the medical records. ECOG-Performance status of the patients were all 3 or less. The patients with history of another primary or hematological disorder were not included. Hematological and biochemical parameters were in normal ranges for all the patients and there was not any other malignancy or hemorrhagic disease of any patient.
"SPSS 15.0 for Windows" software was used for the statistical analysis. Frequency tables for categorical data; descriptive statistical mean, standard deviation, median, minimum and maximum values for quantitative values were prepared. Cross table statistics and chi-square analysis were used to evaluate the differences of the categorical data of the groups. For the analysis of comparison of two quantitative data groups, t-test was used in case of normal distribution and Mann-Whitney U test was used if the data was nonhomogenous. For the analysis of groups having more than two variables, Kruskal-Wallis test was used, because these data were not normally distributed. Relations between the quantitative data was analyzed with Spearman correlation test. PFS was analyzed with Kaplan-Meier Survival Analysis. P-values less than 0,05 were accepted as significant.
| » Results|| |
The patients' ages were between 38-77 years (median 56). Sixty of the patients were male and 7 were female. All of them were diagnosed as SCLC both histopathologically and immunohistochemically. Twenty two of them (32.8%) had limited stage (LS) and 45 (67.2%) had extended stage (ES). No statistically significant difference between the limited and extensive disease groups were observed in terms of age, sex, tobacco consumption, therapy protocols, number of therapeutic cycles, duration of dalteparin usage, rates of response, progression rates during the follow-up period and mean follow-up durations [Table 1]. No difference was detected in PFS between LS and ES [Table 2]. Overal survival was statistically different between the groups [Table 3].
Sixty five of the patients (97.0%) were treated with CE (cisplatin-etoposide) protocol and 2 of them (3.0%) were given CEV (cyclophosphamide-epirubicin-vincristine) protocol. Mean number of chemotherapy cycles was 5.1 (SD = 1.5). Mean duration of dalteparin treatment was 6.1 months (SD = 3.0). Duration of dalteparin therapy was less than 4 months in 19.7% (Group A), between 4-6 months in 60.6% (Group B) and more than 6 months in 19.7% (Group C) of the patients. Fifteen patients (22.4%) took radiotherapy for their primary tumor and 6 patients (9.0%) took radiotherapy for their metastazes, one patient took radiotherapy for both the primary and metastatic tumors.
Complete response was observed in 10.6%, good partial response in 3.0%, partial response in 36.4%, stable disease in 10.6% and progressive disease in 39.4% of the patients. Paraneoplastic syndromes occured in five patients (7.5%) (2 syndrome of inappropriate ADH secretion, 2 superior vena cava syndrome, one idiopathic trombocytopenic purpura). 23.9% of the patients received secondary chemotherapy. Mean duration of follow-up was 11.3 months (SD = 8.6). Progression was observed in 73.1% (n = 49) of the patients and all of the patients died during the follow-up period.
Mean survival was 6.5 months (SD = 4.8 months) (median = 5 months) in Group A; 11.8 months (SD = 8.4 months) (Median = 10 months) in Group B; and 14.6 months (SD = 10.9 months) (Median = 10 months) in Group C [Table 4]. Duration of dalteparin usage resulted with statistically significant (P = 0.001) differences between the groups in terms of survival. Mean survival time was significantly higher in Groups B and C (P < 0.001 for both) than Group A [Table 5]. Nevertheless, there was no statistically significant difference between the groups B and C (P = 0.037; Mann-Whitney U test significance margin P < 0.017) [Figure 1].
The estimated median PFS of the patients was 9 months (SEM = 0.7, 95% Confidence Interval CI = 7.6-10.4)[Figure 2]. Sixth month PFS rate was calculated as 72.9% (SEM = 5.7%), 2-years PFS-rate was 3% (SEM = 2.9%)
The estimated median PFS was statistically significantly different between groups (In Group A: 6 months [SEM = 1.4 95% CI 3.2-8.8], Group B: 9 months [SEM = 0.9, 95% CI 7.2-10.8] Group C: 10 months [SEM = 1.1 95% CI 7.9-12.1], P = 0.028) [Figure 3]. One-year PFS rate was calculated as 17.6% (SEM = 14.8%) in Group A, 12.7% (SEM = 6.5%) in Group B and 32.3% (SEM = 6.5%) in Group C.
According to the univariate Cox Regression analysis model, using dalteparin more than 6 months is statistically significantly more protective, compared to using dalteparin less than 4 months (P = 0.016, Hazard Ratio (HR) = 0.273 95% CI 0.095-0.783). This effect is also significant when corrected with the stage of the disease (P = 0.018, HR 0.282, 95% CI 0.099-0.808).
Side effects occurred in 40.3% of the cases. Grade 3-4 side effects were; neutropenia 31.3%, anemia 4.5%, nausea and vomitting 4.5%, neutropenic fever 1.5% [Table 6].
| » Discussion|| |
Venous thromboembolism (VTE) is one of the important complications of cancer and seen in 4-20% of the patients. [ 10 ] Thromboembolic event can even be the first symptom of the patients. [11 ] Thromboembolic events are seen 1.3-.2 times more in cancer patients than normal population. , VTE (consists of deep vein thrombosis [DVT] and pulmonary embolism [PE]) risk increases several times in cancer patients. 
Chemotherapy is reported to cause increment of thromboembolic event incidence even among the cancer patients in out-patient clinics and these thromboembolic events are seen to be one of the most important reasons of death.  VTE found at the time of the diagnosis or in 1-year period after the diagnosis is associated with 3 times increment in 1-year mortality. 
Hospitalisation and initiation of chemotherapy are the greatest risk factors for VTE in cancer patients. The previous studies showed that the risk of thrombosis for the cancer patients was 4.1 times more than normal, and with chemotherapy this risk increases by 6.5 times. ,,,,
LMWH usage is suggested for thromboembolism prophylaxis in immobile patients, according to the PREVENT study.  In our clinic also LMWH is used for thrombosis prophylaxis in SLCL cases.
LMWH (dalteparin, 200IU/kg/day s.c., 5 days a week for 6 months) was shown to be more effective than oral anticoagulants (coumadin for 6 months, INR 2.5) in terms of decreasing relapse thromboembolism in cancer patients, according to the CLOT study. 
LMWH and fractioned heparin were compared in some studies in the prevention of DVT in cancer patients. Efficacies of the both drugs were shown to be similar, in terms of prophylaxis. ,,
Five thousand units a day dalteparin usage decreases venous thromboembolism rate by half (45% effective, P = 0.0015) and risk of bleeding remains low.  LMWH was shown to decrease the asymptomatic venous thrombosis by the MEDENOX study. 
Some studies in literature claims that usage of LMWH is associated with a little but statistically significant increment of survival, compared with standart heparin. ,
The FAMOUS study showed that daily usage of 5000 units of dalteparin -when compared to placebo- was associated with a statistically insignificant advantage in 1 st , 2 nd and 3 rd years in Stage III-IV cancer patients (lung, breast, gastrointestinal tumors and others) taking chemotherapy or radiotherapy. 
Most of the clinical trials showed that coagulation cascade was activated in SCLC. Zacharski et al. showed that addition of warfarin to the combination chemotherapy increased survival significantly in SCLC but not in other types of tumors. 
According to the meta-analysis done by Lazo-Langner et al. in 2007, LMWH increases the survival in cancer patients, including the advanced stage patients. Authors included 4 methodologically appropriate placebo-controlled randomized controlled trials. 898 patients having solid tumors and took LMWH or placebo are investigated in this study. In 3 trials, dalteparin in prophylactic dosage (5000 units/day) and in one trial, nadroparin was given to the patients for 6 weeks. First- and second-year mortality analysis showed that LMWH reduces the death risk of all patients by 30% (P = 0.05) and 43% (P = 0.03) respectively. In advanced stage patients, the risk reduces 25% (P = 0.04) and 41% (P = 0.03), respectively. Total hazard ratio was 0.83 (P = 0.03) in all patients and 0.86 (P = 0.04) in advanced stage patients, in favor of LMWH. 
These results prove that LMWH increases the survival in cancer patients, including advanced stage.
In a randomized controlled trial comparing oral anticoagulant with LMWH, the patients with solid tumors were given LMWH or coumadin derivative for 6 months and the prophylactic response against relapsing thromboembolism was assessed (The CLOT Trial). The post-hoc analysis of this trial showed that metastases were seen in 20% of dalteparin taking group and 36% of coumadin taking group; 50% decrease of mortality was observed in dalteparin taking group. 
Heparin expresses the specific apoptotic gene and induces apoptosis.  LMWH blocks the systemic angiogenesis.  In experimental tumor models, LMWH was shown to be more effective on tumor growth than fractioned heparin.  It is possible that coagulation factors enhance tumor growth.  There is a close relation between hemostatic system and cancer. In experimental models, it was shown that over expression of tissue factor enhances thromboembolic events and also in vivo tumor growth and in vitro tumor invasion. 
A previous study showed that LMWH (dalteparin) added to the chemotherapy successfully inhibits DVT in SLCL patients. Also, combination therapy with dalteparin is associated with statistically significant survival advantage in SCLC. The dose of dalteparin given was 5000 units/day and cyclophosphamide-epirubicin-vincristine combination was given as chemotherapy. Objective response was only 42.5% when the chemotherapy was used alone, and 69.2% when the chemotherapy was combined with dalteparin. The result was statistically insignificant (P = 0.07), but an increase in survival was observed. PFS increased significantly (6 months vs. 10 months) (P = 0.01) and OS increased significantly (8 months vs 13 months) (P = 0.007) in favor of dalteparin. The response rate to the combination of chemotherapy with LMWH was high, especially in local disease. Response rate to the combination of chemotherapy with LMWH, both in terms of OS and PFS was significantly higher in both limited (for PFS P = 0.025; for OS P = 0.007) and extensive-stage disease (for PFS P = 0.012; for OS P = 0.012). 
In this study, it is shown that combination of LMWH more than 4 months increases OS and PFS in SCLC cases significantly with comparison to LMWH usage less than 4 months. It is notable that this therapeutic approach is well-tolerated.
The advantages of LMWH usage in advanced solid tumors are assessed in a review.  A meta-analysis including 4 placebo-controlled randomized trials on 898 patients also showed that LMWH increases survival rates in advanced solid tumors. 
American College of Chest Physicans (ACCP), suggested VTE prophylaxis in hospitalized patients in the 7 th concencus meeting in 2004. 
The last Italian suggestion for VTE prophylaxis was published in 2006 by Italian Association of Medical Oncology. According to this publication, anticoagulant therapy is suggested after the risk-benefit analysis and considering 6 different situations (VTE due to occult tumor, VTE prophylaxis in cancer surgery, VTE prophylaxis during chemotherapy or hormonotherapy, VTE prophylaxis in case of central vein catheter insertion, VTE and anticoagulant therapy in cancer patients and prognosis of cancer). 
American Society of Clinical Oncology (ASCO) suggests anticoagulant prophylaxis in all hospitalized cancer patients when bleeding, ulcer, stone and other contraindications are absent. 
National Comprehensive Cancer Network's (NCCN) last suggestion about VTE was announced in March 2006 (the internet site for reference: http://nccn.org/professionals/physician_gls/PDF7vte.pdf). 
It is reasonable to think that usage of LMWH in SCLC is beneficial for the treatment and prophylaxis of thrombosis and also for survival. According to our studies, observations and the literature; the standart approach to the SCLC treatment must be combination of chemotherapy with LMWH. Multicentered prospective randomized controlled trials must be done immediately to provide the definitive evidence.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]
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