Prospective Investigation of Tumor
Markers and Risk Assessment in
Early Cancer Screening

Tsuneo Kobayashi, M.D., and Tomoko Kawakubo, M.Sc.

Background. Many researchers have reported that tumor marker diagnosis may not be useful in the early detection of cancer. However, the authors proposed a new diagnostic system using a tumor marker combination assay.

Methods. The authors screened an asymptomatic population (2126 subjects) in Japan for early cancer over a 2-year period (1984-1986) using this tumor marker combination assay. The serum tumor marker combination assay data were analyzed: tumor-specific tumor markers (carcinoembryonic antigen, carbohydrate 19-9, heatstable alkaline phosphatase, and tissue polypeptide antigen), tumor-associated tumor markers (ferritin, the ratio of ferritin to serum iron, immunosuppressive acidic protein, sialic acid), and growth-related tumor markers (alkaline phosphatase isoenzymes, ribonuclease). The tumor growth levels of the subjects were assessed by the tumor marker combination assay and classified into five tumor stages (Stage I, tumorfree; Stages II-III, precancer; Stage IV, preclinical cancer; Stage V, suggestive of cancer weighing over 1 g). The follow-up period was 5-7 years.

Results. The percentage of subjects in tumor stages IV and V increased with age, whereas the percentage in tumor stages II and III decreased. The distribution of screenees within each tumor stage was as follows: 1, 0.1%; 11, 11.8%; III, 58.8%; IV, 24.8%; V, 4.6%. The rate of incidence of cancer for Stages V, VI, III, It and I was 29.5% (28 of 95),2.7% (14 of 528),0.7% (9 of 125110.4% (1 of 250), and 0 (0 of 2), respectively.

Conclusions. Our tumor stage classification can adequately assess the risk of cancer developing in apparently healthy persons. Cancer 1994; 73:1946-53.

Key words: tumor markers, tumor stage, risk assessment, incidence of cancer.

Many researchers have reported that tumor marker diagnosis may not be useful in the early detection of cancer because of its low sensitivity (percentage of subjects diagnosed as having cancer among patients with cancer) and specificity (percentage of subjects who are not diagnosed as having cancer among normal, healthy subjects). However, we have proposed a new diagnostic system consisting of a tumor marker combination assay (using specific tumor markers, associated tumor markers; and growth-related tumor markers).' With this new diagnostic system, we have obtained high sensitivity (80-91%) and high specificity (84-85%).2 In June 1984, we started a program of substantial tumor marker-based cancer screening using this tumor marker combination assay, which lasted approximately 2 years.
Japan has many screening facilities for cancers of the stomach, lung, uterus, and breast, cancers that are both widespread and generally detectable using conventional morphologic techniques for neoplasms weighing 1 g or more. In contrast to the United States and Europe, where cancer screening is not highly evaluated, it is used extensively in Japan, receiving financial support and promotion from national and local governments as well as the private sector. Conventional stomach and uterine cancer screening techniques, such as radiograph and the Papanicolaou test, obtained a cancer detection rate of only 0.150 (40,200 of 26,733,815 screenees) and 0.092 (25,620 of 27,834,585), respectively.' This incidence of cancer in the general population using conventional morphologic techniques is low. This is not because the techniques are poorly used or administered to the wrong target sample, but because of their limitations, for example, their dependence on the visual characteristics, size, and site of the cancer.
The growing neoplasm consists of a cancer cell cluster, a cancer-supporting stroma,4,5 and cancer vessels,6 which produce oncofetal antigen, oncoplacental antigen, and cancer vessel-related substances, respectively. Therefore, we hypothesized that these three substances are important in early cancer detection. Furthermore, because they are identical to tumor-specific tumor markers, tumor-associated tumor markers, and