Japanese Journal of Clinical Oncology 30:174-179 (2000)
© 2000 Foundation for Promotion of Cancer Research
Usefulness of Serum Carboxy-Terminal Telopeptide of Type I Collagen (ICTP) as a Marker of Bone Metastasis from Lung Cancer
Department of Internal Medicine, Fujita Health University School of Medicine, Second Hospital, Nagoya, Aichi, Japan
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ABSTRACT |
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Background: Serum pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen (ICTP) is a metabolite of type I collagen comprising 90% or more of organic substances in bone. Its usefulness as a marker of bone metastasis from malignant tumors is expected.
Method: We measured ICTP to evaluate its clinical usefulness for diagnosis of bone metastasis in 140 patients with lung cancer. For comparison, serum carcinoembryonic antigen (CEA), cytokeratin 19 fragment (CYFRA 21-1), gastrin-releasing peptide precursor (ProGRP), alkaline phosphatase and calcium were simultaneously measured. ICTP was measured by double-antibody radioimmunoassay.
Results: ICTP was significantly higher in patients with bone metastasis from lung cancer than in the group without bone metastasis, patients with other pulmonary diseases or healthy control subjects and showed excellent sensitivity and specificity, indicating that this marker is highly useful for complementary diagnosis of bone metastasis from lung cancer. Moreover, the survival duration was significantly shorter in the ICTP-positive group than in the ICTP-negative group, suggesting that ICTP can be a prognostic factor in lung cancer.
Conclusion: It is suggested that measurement of ICTP is worthwhile as a serological diagnostic method of bone metastasis from lung cancer. Moreover, since repeated measurements are possible, this measure was considered very helpful in complementary diagnosis of bone metastasis and also as a standard to determine the timing of examinations such as bone scintigraphy.
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INTRODUCTION |
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Metastatic bone disease is the most dominant bone lesion seen in adult patients with malignancy. The major collagen in bone is type I collagen, which is synthesized by osteoblasts and accounts for about 90% of the organic matrix (1,2). This collagen is formed as a large precursor protein, type I procollagen. Assay of the carboxy-terminal propeptide of type I procollagen (PICP) is a test with which it is possible to follow the synthesis of type I collagen (2). In addition, a bone resorption assay has recently been developed which is based on cross-linked peptide liberated during type I collagen degradation (ICTP). Its usefulness as a marker of bone metastasis from malignant tumors is expected. In this study, we examined the usefulness of ICTP as a marker of bone metastasis by measuring serum ICTP in patients with lung cancer.
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SUBJECTS AND METHODS |
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The subjects consisted of 140 patients with lung cancer (38 patients with squamous cell carcinoma, 64 patients with adenocarcinoma, two patients with large cell carcinoma; clinical stage IIIa in 17 patients, stage IIIb in 11 patients, stage IV in 76 patients, 36 patients with small cell carcinoma; clinical stage Limited Disease none, Extensive Disease in 36 patients), ranging in age from 37 to 88 years (mean, 69.7 years). Controls were 50 patients with other pulmonary diseases [six patients with obsolete pulmonary tuberculosis, 16 patients with chronic pulmonary emphysema, 12 patients with bronchial asthma, six patients with idiopathic interstitial pneumonia (IIP), 10 patients with bacterial pneumonia], ranging in age from 39 to 78 years (mean, 60.0 years) and 40 healthy subjects, ranging in age from 25 to 79 years (mean, 51.0 years). Bone metastasis was comprehensively diagnosed using bone X-P, bone scintigraphy, CT and MRI and 100 of 140 patients were positive for bone metastasis.We diagnosed patients with or without bone metastasis by bone CT or MRI when the bone scintigraphy was positive and without pain. Autopsies were not performed.
Patients with diseases such as hypercalcemia, hyperthyroidism, rheumatoid arthritis and fractures that may affect bone turnover were excluded from this study.
Serum ICTP was measured by double-antibody radioimmunoassay using pyridinoline ICTP (Chugai Pharmaceutical). Simultaneously, serum calcium (Ca), serum alkaline phosphatase (Alp), serum carcinoembryonic antigen (CEA), serum cytokeratin 19 fragment (CYFRA 21-1) and gastrin-releasing peptide precursor (ProGRP), which have been reported to be useful tumor markers in lung cancer, were also determined. The cutoff values were set at 4.5 ng/ml for ICTP, 10.2 mg/dl for Ca, 80 mU/ml for Alp, 2.5 ng/ml for CEA, 3.5 ng/ml for CYFRA 21-1 and 46.0 pg/ml for ProGRP. Serum was separated from blood samples immediately after blood collection and cryopreserved at –20°C. Apparent hemolytic serum was excluded. Results were expressed as mean ± SE. Comparisons between two groups were statistically assessed using the Mann–Whitney U-test and those among the three groups were analyzed using ANOVA.
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RESULTS |
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ICTP in Lung Cancer, Other Pulmonary Diseases and Healthy Controls (Fig. 1)
ICTP was 10.9 ± 0.88 in patients with bone metastasis from lung cancer, 4.35 ± 0.02 in patients without bone metastasis, 3.03 ± 0.17 in other pulmonary diseases and 2.82 ± 0.14 in healthy controls, showing higher values in patients with lung cancer, in particular, demonstrating significantly higher values in patients with bone metastasis.
Tumor Markers in Lung Cancer with/without Bone Metastasis (Fig. 2)
There was no significant difference in each tumor marker between the two groups.
Ca and Alp in Lung Cancer with/without Bone Metastasis (Fig. 3)
There was no significant difference in each marker between the two groups.
Correlation Between ICTP and CEA, CYFRA 21-1, ProGRP, Ca or Alp
There was no significant correlation between ICTP and each marker.
Sensitivity, Specificity and Accuracy of Various Markers in Lung Cancer (Table 1)
ICTP demonstrated a sensitivity of 92.0%,a specificity of 70.0% and an accuracy of 81.6%, showing the highest sensitivity and accuracy among all markers.
ICTP for Each Histological Type in Patients with Bone Metastasis from Lung Cancer
ICTP for each histological type did not show any consistent tendency.
ICTP by the Extent of Bone Metastasis (Fig. 4)
ICTP levels were compared, taking no bone metastasis as grade 0, one bone metastasis as grade 1, 2–5 bone metastases as grade 2 and 
6 bone metastases as grade 3. ICTP was significantly increased even in grade I and showed higher values with further advances of the grade.
Tumor Markers by the Extent of Bone Metastasis (Fig. 5)
Each marker by the extent of bone metastasis showed no consistent tendency.
Ca and Alp by the Extent of Bone Metastasis (Fig. 6)
Ca and Alp by the extent of bone metastasis showed no consistent tendency.
Survival Curves in lung Cancer (Figs. 7 and 8, Table 2)
Patient backgrounds in the ICTP-positive group (4.5 ng/ml) and ICTP-negative group (<4.5 ng/ml) are shown in Table 2. The positive and negative groups were composed of 104 patients and 36 patients, respectively, and there were no significant differences in background factors between the two groups. The survival duration was significantly shorter in the ICTP-positive group than in the ICTP-negative group in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). There was no significant difference in other markers between the two groups.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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For diagnosis of bone metastasis, diagnostic imaging techniques include mainly bone scintigraphy, but CT, MRI and plain radiography are also used. However, the sensitivity of plain radiography is not satisfactory. Bone scintigraphy is an excellent diagnostic measure, but is used in a very limited number of institutions and has the disadvantage of showing a positive reaction even to bone inflammation and fractures. Both CT and MRI cannot be easily performed because of problems of cost and time. Therefore, many recent reports have described outcomes regarding diagnosis of bone metastasis and observation of the clinical course using markers of bone turnover (3–6).
Since blood levels of ICTP reflect the amount of bone resorption in bone tissue, ICTP is categorized as a marker of bone resorption among markers of bone turnover and considered clinically helpful in diagnosing bone metastasis of malignant tumors. Yamamoto et al. measured ICTP in patients with lung cancer who developed mainly osteolytic bone metastasis that induces bone destruction and demonstrated the usefulness of ICTP in detecting bone metastasis, understanding the pathology and evaluating therapeutic effects (7). We therefore examined the usefulness of ICTP as a marker of bone metastasis in patients with lung cancer.
The results demonstrated that ICTP was significantly higher in the group with bone metastasis than in the group without bone metastasis, among patients with lung cancer. There was no significant difference in any simultaneously measured marker, CEA, CYFRA 21-1, ProGRP, Ca or Alp, between the presence and absence of bone metastasis. Furthermore, ICTP was not correlated with any other markers and showed excellent sensitivity, specificity and accuracy, suggesting the usefulness for diagnosis of bone metastasis from lung cancer. Even in the group without bone metastasis, ICTP was significantly higher in patients with lung cancer than in healthy control subjects and patients with non-malignant pulmonary diseases. This result seems to suggest a potential for reflecting bone micrometastasis. As for grade 0 in ICTP positive patients, bone metastasis is revealed with bone scintigraphy in most cases by sequential observation and, therefore, when ICTP is increased even in asymptomatic patients without discernible bone metastasis, sufficient observation of the clinical course appears necessary, considering potential bone metastasis (8). ICTP by histological type did not show any consistent tendency. Comparison of ICTP by the extent of bone metastasis revealed that even some patients with grade I tumors were positive for ICTP and ICTP increased with advances of the grade, suggesting that this parameter may be useful for complementary diagnosis for early detection of bone metastasis and observation of the clinical course. As a study of the prognosis, Gravenstein et al. described that 40 of 46 patients positive for bone metastasis on bone scintigraphy died within 6 months, suggesting that bone metastasis is a factor in predicting a poor prognosis (9). In the present study also, survival curves in patients with lung cancer (NSCLC, SCLC) demonstrated that the survival duration was significantly shorter in the ICTP-positive group than in the negative group at the time of diagnosis of lung cancer, although the number of patients was limited. This finding suggests that elevation of ICTP can be a factor in predicting a poor prognosis.
In conclusion, it is suggested that sequential observation of ICTP is a highly useful means of evaluating the presence or absence, progression and aggravation of bone metastasis in patients with lung cancer. Moreover, since repeated measurements are possible, this measure was considered very helpful in complementary diagnosis of bone metastasis and also as a standard to determine the timing of examinations such as bone scintigraphy.
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FOOTNOTES |
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+ For reprints and all correspondence: Takahiko Horiguchi, Department of Internal Medicine, Fujita Health University School of Medicine, Second Hospital, 3–6–10, Otobashi, Nakagawa-ku, Nagoya, Aichi 454-0012, JapanAbbreviations: ICTP, carboxy-terminal telopeptide of type I collagen; CEA, carcinoembryonic antigen; CYFRA 21-1, cytokeratin 19 fragment; ProGRP, gastrin-releasing peptide precursor; PICP, carboxy-terminal propeptide of type I collagen; IIP, idiopathic interstitial pneumonia; Ca, calcium; Alp, alkaline phosphatase; NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer
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REFERENCES |
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Received October 26, 1999; accepted January 26, 2000.
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