PROGNOSTIC SIGNIFICANCE OF BLOOD COAGULATION TESTS IN LUNG CANCER

From the (*) Cuneo Lung Cancer Study Group (www.culcasg.org), at the Division of Respiratory Medicine,  "S. Croce e Carle" Hospital, I-12100 Cuneo, Italy, (§) Department of Oncology-Haemathology,"San Giovanni Battista" Hospital, I-10126 Torino, Italy

 The correspondence regarding the manuscript should be sent to:

Domenico Ferrigno, MD, Divisione di Pneumologia, Ospedale "S.Croce e Carle", I-12100 Cuneo, Italy, Tel.: + 39.171.441733, Fax: + 39.171.441764, E-mail: ferrigno@culcasg.org

Running Head: HAEMOSTATIC ABNORMALITIES IN LUNG CANCER

Key words: Lung cancer, prognosis, blood coagulation, pre-thrombotic state

Many authors demonstrated that activation of coagulation has an impact on the clinical course of lung cancer.

This study was carried out in order to assess the potential prognostic significance of platelet count (P), prothrombin time (PT), partial thromboplastin time (PTT), anti-thrombin III (AT-III), fibrinogen (F), D-dimer (DD), factor II (F-II), factor VII (F-VII), factor X (F-X), protein C clotting (PCC), plasminogen (PL), and antiplasmin (AP) in 343 consecutive new lung cancer patients, , during the last 4 years. A set of 32 anthropometric, clinical, physical, laboratory, radiological, and pathological variables was prospectively recorded for all patients. Patients were carefully followed-up, and their subsequent clinical course recorded.

The most frequent abnormalities regarded DD, F, and AT-III (55, 42, and 28% of the cases), followed by F-VII (27%), F-X (20%), and F-II (16%). Among the 12 clotting variables, the strongest relationships were those of F-II and F-X (r_s=0.565), PT and F-VII (r_s=0.562), F-VII and F-X (r_s=0.514), PL and AP (r_s=0.515), F and P (r_s=0.490), AT-III and PCC (r_s=0.476). Univariate analyses of survival showed that prolonged values of PT (p<0.043), and abnormally elevated values of DD (p<0.003), F (p<0.031), and P (p<0.047) were all associated with a bad prognosis. The multivariate model, on the contrary, did not confirm the prognostic capability of the coagulation factors.

This data indicates that there has been a subclinical activation of blood coagulation in lung cancer patients since the early clinical stages of the disease. In addition, the clotting activation is confirmed as predictor of survival, although not independently of the other prognostic factors.

After the first reports by Trousseau ¹, biological data and several experimental works have shown that an important relationship does exist between the neoplastic growth and the phenomena linked to blood coagulation ^2-4. Generally, patients with cancer present abnormalities with one or more circulating markers of haemostasis activation, underlying a hypercoagulable state. However, the biochemical basis of this phenomenon is not completely understood ^{4; 5}. The potential role of the clotting-fibrinolytic system in the pathogenesis of malignancy, tumour growth regulation and cancer cell dissemination has been already suggested ²³. Anticoagulant therapy has been reported to suppress the invasion of cancer cells in experimental models, showing clinically survival benefits in some types of tumour when used in combination with chemotherapy ^6-8. Also in lung cancer, systemic activation of the clotting system frequently occurs^2-4. Clotting abnormalities have been shown to correlate with tumour burden, clinical progression, and the response to chemotherapy ^{2; 4; 7; 9; 10}. We recently reported that a number of coagulation factors [i.e. prothrombin time, fibrinogen, and D-dimer] are important independent predictors of survival ³.

The purpose of this new study was to: i) confirm our previous data; ii) assess other coagulation-fibrinolytic factors and evaluate their subclinical activation; iii) define the possible correlation between such abnormalities and other clinical and laboratory characteristics; and iv) investigate the prognostic value of pre-treatment plasma levels of such haemostatic abnormalities.

Patients

From January 1996 to December 1999, 343 consecutive unselected patients (304 men and 39 women, median age 68 years – range 39-86) with histologically proven bronchogenic carcinoma, were referred to the division of Respiratory Diseases of the " S. Croce and A. Carle Hospital" of Cuneo. The pathological diagnosis of primary lung cancer was carried out in accordance with the revised WHO classification of lung tumours ¹¹ and included 125 squamous cell carcinomas, 80 adenocarcinomas, 34 small cell carcinomas, 16 large cell carcinomas, and 88 unclassified carcinomas. All patients were classified according to the 1997 staging system ¹². Pre-treatment clinical evaluation was based on physical examination, weight loss determination and the Eastern Cooperative Oncology Group (ECOG) performance status ¹³. A battery of laboratory tests, including coagulation tests, was routinely requested. The instrumental evaluation consisted of x-rays, fibroptic bronchoscopy and computed tomography of chest, upper abdomen and brain. In potentially resectable tumours, any radiological finding equivocal for nodal mediastinal involvement was considered an indication to mediastinoscopy. Patients with dubious metastatic involvement were further investigated with appropriate imaging studies, biopsies or needle aspirations. Bone scan and bone marrow biopsy were performed in most small cell lung cancer (SCLC) patients. As foreseeable, only a relatively small fraction of patients could be surgically treated (19 % of the cohort). Chemotherapy was the most frequent treatment, coherently with our early recognition of its potential benefit ^{14; 15} either alone or in combination (51% of the population). Curative radiotherapy was performed only in 2% of the cases; the remaining patients received the best supportive care (26%). Survival was recorded from the time of histological diagnosis to death, or to the last clinical examination or telephone contact with the patient himself, the family, the family doctor, or the municipal registry office. Consequently, both the duration of survival, measured from the first hospital admission or outpatient examination, and the status of dead or alive at the closure of the study (i.e., at the end of December 1999) was recorded for all patients. As per December of 1999, 71 patients (21%) were still alive, after a median follow-up time of 8.5 months (quartile range 3.6-17.4).

Study design

This was a prospective study. We recorded 32 variables for each patient entered on study, including the following twelve coagulation factors: platelet count (P), prothrombin time (PT), partial thromboplastin time (PTT), anti-thrombin III (AT-III), fibrinogen (F), D-dimer (DD), factor II (F-II), factor VII (F-VII), factor X (F-X), protein C clotting (PCC), plasminogen (PL), and antiplasmin (AP). The other variables on record were age, sex, ECOG performance status, weight loss, haemoglobin blood content, total white cell/neutrophil counts, tumour cell type, clinical stage, and the T, N, and M factor. In addition, we measured and recorded the serum concentration of each of the following enzymes and substances: lactate dehydrogenase, alkaline phosphatase, pyruvic and oxalacetic transaminases, creatinine, sodium, carcinoembryonic antigen, and tissue polypeptide antigen ¹⁶. Follow-up programs consisted of clinical, laboratory, and radiological reassessments performed at 3-4 weeks intervals during chemotherapy, and every three to six weeks in case of palliative radiotherapy, or no anti-cancer treatment. Patients treated with radical surgery were scheduled for examination at longer intervals, ranging 3-6 months.

Coagulation assays

Commercially available reagents provided by the DIAGNOSTICA STAGO, Boehringer Mannheim Co., (Germany) were used to measure PT (STA Neoplastin Plus kit), PTT (STA APTL LT kit), AT-III (STA Antithrombin III kit), F-II (STA Factor II kit), F-VII (STA Factor VII kit), F-X (STA Factor X kit), PCC (STA Protein C Clotting kit), DD (STA LIATEST D-DI kit), and F (STA Fibrinogen kit). . The reagents DIAGNOSTICA STAGO (France) were used to measure plasminogen (STA-STACHROM PLASMINOGEN kit) and antiplasmin (STA-STACHROM ANTIPLASMIN kit). For all determinations, the manufacturer’s instructions were followed. Patients’ blood samples were obtained at presentation and processed immediately, or stored for a maximum of 2 days at –20° C until needed.

Statistical analysis

Statistical analysis was performed using the SPSS package for Windows, Version 9.0 (SPSS Inc., Chicago, IL, USA). Non-parametric tests ¹⁷ were used to assess statistically relationships and differences among coagulation factors or between these factors and the other variables recorded (i.e. Spearman rank, Kruskall-Wallis, and median test, as appropriate). Survival curves were obtained with the Kaplan-Meier method ¹⁸ and compared by means of the log-rank test ¹⁹. Multivariate survival analyses were made using the Cox's proportional hazards regression model ²⁰. For continuous variables, categorisation was accomplished using the median value as cut-point. The significance of each factor was calculated by the maximum likelihood ratio. A p value of 0.1 was set to enter, while a value of 0.15 was set to remove a variable from the model. A p value of less than 0.05 was regarded as statistically significant. All tests were two-sided.

Results

Almost all the pre-treatment laboratory parameters for this study plus 9 clinical variables and the twelve coagulation tests were available for the 343 documented patients with lung cancer. More in detail, the number of observations and, either the frequency or the median and range for all the clinical and laboratory variables considered are reported in table 1. The same parameters plus the number of normal, low, and abnormally high values for all clotting tests are given in table 2.

Forty-four patients (13%) had manifest thrombocytosis (=>400.000/mm3), while 9 (3%) were thrombocytopenic (<150.000/ mm3). In 15 cases (4%) PT was below the 70% of the reference value. Ten patients (3%) had frankly reduced times of PTT (<25 sec.), and in only 7 PTT (2%) were above 40 sec. F-II, F-VII, F-X were abnormal (>100%) in 55 (16%), 90 (27%), and 66 (20%) patients, respectively. Increased values of F, DD, and AT-III were found in 143 (42%), 182 (55%), and 92 (28%) cases, respectively. A small number of patients had increased values of PL (8%), PCC (6%), and AP (3%). No coagulation factor showed abnormalities based on the cell type (p values of the differences were comprised between 0.49 and 0.07, Kruskall-Wallis test). The best relationship between clinical and laboratory variables were those of ECOG-PS with weight-loss (Spearman r [r_s]=0.236), and stage of disease (r_s=0.109). Other significant associations were those between ECOG PS and AT-III (r_s=-0.157), F (r_s=0.142), F-II (r_s=0.141), F-X (r_s=0.136), and DD (r_s=0.113). The stage of disease was related to P (r_s=0.124) and F (r_s=0.130), while weight loss was correlated with F (r_s=0.131) and AT-III (r_s=0.120). Bivariate correlation tests among the 12 clotting variables revealed several significant associations (table 3). In particular, the strongest relationships were those between F-II and F-X (r_s=0.565), PT and F-VII (r_s=0.562), F-VII and F-X (r_s=0.514), PL and AP (r_s=0.515), F and P (r_s=0.490), AT-III and PCC (r_s=0.476). Other frequent and significant relationships were those between F-II, F-VII, F-X and PCC, PL, AP, AT-III (Table 3). DD was only related to F-II and AP (r_s=-0.113/-0.112).

Univariate analyses of survival confirmed the already known relationships between survival and stage of disease, TNM factors, ECOG PS and weight loss (all tests with p values less than 0.001). Conversely, AP (p=0.987), PL (p=0.935), F-II (p=0.465), PTT (p=0.458), PCC (p=0.297), F-X (p=0.173), AT-III (p=0.115), and F-VII (p=0.114) were unrelated to the patients’ outcome. Patients with values of fibrinogen below 447 mg/dl had significantly longer survivals than patients with values above the median (10 months, 95% confidence intervals (CI): 7-13, vs 8 months, CI: 7-10, p<0.031)(fig. 1). Similarly, abnormal elevated concentrations of DD were strongly predictive of a poor prognosis (7 vs 10 months, CI: 6-9 and 8-12 respectively, p<0.003)(fig. 2). Patients with PT values above 90% had a short median survival (7.7 months, CI: 6-9), as compared with the 10 months of the remaining subjects (CI: 9-12, p<0.043)(fig. 3). Also, patients with platelets values above 289.000 mm³ survived less (8 months, CI: 7-10) than patients with lower counts (10 months, CI: 6-13, p<0.047)(fig. 4). Multivariate analyses of survival were accomplished with no prior dichotomization or categorisation of the continuous variables. A Cox’s proportional hazards regression analysis, including 293 cases and all the 32 considered variables, selected, as prognostically significant, in order of descending importance: 1) stage of disease; 2) ECOG PS; 3) lactate dehydrogenase; 4) neutrophils; 5) tissue polypeptide antigen; and 6) creatinine (table 4).

In lung cancer, prognostic factors are helpful in advising individuals, choosing treatments, understanding the disease and providing direction of further study. Traditionally, a number of baseline clinical characteristics such as the anatomical extent of the disease, performance status and weight loss have been used to predict the outcome in individual patients ²¹. The purpose of this prospective study was to determine the possible prognostic value of twelve tests of blood coagulation (i.e., P, PT, PTT, AT-III, F, DD, F-II, F-VII, F-X, PCC, PL, and AP).

The blood coagulation scheme has been divided into two pathways, "extrinsic" and "intrinsic", both of which converge into a final common pathway for the production of thrombin. Although it is operationally convenient to think of these as separate, many of their reactions suggest a fair amount of "crosstalk" between the two pathways. The term "extrinsic" implies that extravascular substances are required to initiate blood coagulation; "intrinsic" indicates that all components required to trigger blood clotting are contained within the vascular system ²². Approximately 90% of cancer patients with metastatic disease and half of all cancer patients have abnormal coagulation parameters ²³. Several laboratory abnormalities including prolonged and shortened PT and PTT, increased and decreased levels of F, F-V, F-VIII, F-IX, F-XI, F-XII, fibrinogen, fibrinogen/fibrin degradation products, thrombin-antithrombin III complex, and thrombocytosis have been reported ²³. Thrombocytosis is found in patients with metastatic disease and has been related to extensive disease either in lung cancer or in other malignancies ²⁴. Recently, Pedersen et al. ²⁴ reported increased platelet counts in 32% of 1.115 patients with primary lung cancer, and showed that thrombocytosis was prognostically significant. In our cohort, we found an elevation of the platelet count above 400.000/m3 in 44 of the 343 assessable cases (13%) and a poor prognosis was found for those with platelet counts above the median. Hyperfibrinogenemia is found in the same clinical states that usually accompany thrombocytosis ²². If the F level is normal, a prolonged PT signifies a deficiency of one factor of the extrinsic way (i.e., factor VII), as well as a deficiency of factors common to the extrinsic and intrinsic systems (i.e., factor X, factor V and prothrombin) ²². Alternatively, a prolonged PT may be due to the presence of a specific inhibitor to one of those factors, or a level of fibrin split products sufficiently high to delay fibrin formation ²². In our study, we observed a significant reduction of PT in 15 cases (4% of the sample) and an abnormally prolonged PT was strongly predictive of a bad prognosis. The smallest unique degradation product of cross-linked fibrin is fragment DD (D-dimer) which results from the proteolytic actions of plasmin on fibrin ²⁵. It is considered a sensitive marker of the fibrinolytic enhancement ²⁵. We found that many patients (55%) had an increased plasma level of DD, and this was associated with a poor prognosis. The partial thromboplastin time, assuming a normal fibrinogen level, screens for deficiencies of factors in the intrinsic system (XII, XI, IX, VIII) or deficiencies of factors common to the intrinsic and extrinsic system ²². In our study, only seven of 342 patients had abnormally prolonged PTT.

There are numerous reports indicating that lung cancer patients exhibit an increased propensity to clotting and fibrinolytic system aberrations ^2-4. In addition, clinical and experimental evidences support the idea that the activation of coagulation and fibrinolysis may play an important role in the invasiveness of cancer ²³. Regarding the pathogenetic mechanism of these tumour-associated coagulopathies, many factors have been ascribed as potential causative agents. The activation of the clotting cascade can be due to tumour cells themselves, or to the stimulation of tumour associated inflammatory cells ²⁶. A number of studies have also demonstrated a relationship between coagulation changes and the natural history of malignancies. The hypothesis that anticoagulant therapy may prolong survival of small cell lung cancer (SCLC) patients has been proved ^{6; 7}. In the last few years, several reports have evaluated the possible prognostic significance of blood coagulation ^{10; 27-30}. Meehan et al. ²⁷ have studied 119 untreated SCLC patients and showed that higher pre-treatment fibrinogen levels correlated significantly with advanced stages of disease and reduced survival. In addition, pre-treatment levels were correlated significantly with the likelihood of achieving disease regression after chemotherapy. The group of Seitz ¹⁰ reported that also thrombin-antithrombin complex (TAT) and DD were significantly increased in the metastatic disease, and that elevated TAT values at diagnosis might be prognostically significant. Wojtukiewicz et al. ²⁹ showed that survival is reduced in non-small cell lung cancer patients having elevated value of fibrinogen and fibrin (ogen) split products, platelets count and activated PTT. In patients with disseminated SCLC disease, these authors reported that also prolonged PTTs were associated with a shortened survival. In multivariate analysis, PTT was an independent predictor of survival in limited NSCLC and in disseminated SCLC patients, while fibrin (ogen) split products were significant only in disseminated NSCLC group. Taguchi and co-workers ³⁰ assessed the plasma level of the plasmin-a ₂-plasmin inhibitor complex and showed that its abnormality was predictor of survival independently of stage of disease, sex, age, histological type, performance status, tumour size and presence of distant metastasis. The same author ²⁸ measured the plasma levels of DD in 70 lung cancer patients. Low values of DD were significantly predictive of both good prognosis and longer survival times. We reported, recently, that several clotting tests were predictive of prognosis, in both univariate and multivariate models ³. Univariate tests showed that lower values of PT, higher values of F, and abnormally elevated concentrations of DD were all significantly associated with an adverse outcome. Lower values of PTT were also associated with shorter survivals, but this relationship did not reach the significance level (p=0.1). The multivariate models confirmed several clotting tests as significant ³.

The current study confirms that subclinical changes in the coagulation-fibrinolytic system are often present in lung cancer. The most frequent alterations concern DD, F, AT-III (55, 42, and 28% of the cases), followed by F-VII (27%), F-X (20%), and F-II (16%). Confirming our previous report, univariate analyses of survival showed that a prolonged value of prothrombin time and higher values of platelet count, fibrinogen, and D-dimer are all associated with a poor prognosis. However, in this study, the multivariate model did not confirm the prognostic relevance of any of those coagulation factors. This may be explained by an overshadowing of their prognostic potential by the presence of other more potent known prognostic factors, such as ECOG performance status and TNM-stage Our earlier results showing the independent prognostic significance of prothrombin time and platelets³ are, therefore, not confirmed by the present study, which was carried out on a different cohort sample and with different laboratory methods and based on a different mix of recorded variables.

Further large studies on specific subgroups of lung cancer patients (e.g., we have started a new study in only stage IV chemotherapy patients) are needed to better define the effective prognostic values of the clotting abnormalities and to design additional studies to implement the therapeutic interventions aimed to correct the activation of the clotting-fibrinolytic system.

Acknowledgements:

The authors thank Lorena Gribaudo and Anna Merlo, nurses of their outpatient unit, for the invaluable help and support, and Mrs. Anna Cerchietti for English editing. They are also indebted to the Cuneo Lung Cancer Study Group (Cu.L.Ca.S.G.) for the technical and financial support.

 

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Survival probability based on the result of the fibrinogen test (F). Groups Low,High (no. dead 124,135; no. alive 44,34 respectively)

 

Fig. 3

Survival probability based on the result of the D-dimer test (DD). Groups Low, High (no. dead 107,151; no. alive 44,31 respectively)

Abbreviations: ECOG= Eastern Cooperative Oncology Group; PS= performance status; Y=yes; N=no; E= epidermoid carcinomas; S= small cell lung cancers; A= adenocarcinomas; L= large cell anaplastic carcinomas; U= unclassified carcinomas.

Abbreviations: P= platelets; PT= prothrombin time; PTT= partial thromboplastin time; F= fibrinogen; F-II= factor II; F-VII= factor VII; F-X= factor X; DD= D-dimer; PCC= proteic C clotting; PL= plasminogen; AP= antiplasmin; AT-III= antithrombin III. In black significant results