The rate of growth of human and experimental cancers is initially quite rapid (exponential) and then slows until a plateau is reached. The decrease in growth rate with increasing tumor size is related both to a decrease in the proportion of cancer cells actively proliferating (termed the growth fraction) and to an increase in the rate of cell loss due to hypoxic necrosis, poor nutrient supply, im-munological defense mechanisms, and other processes.
The rate of spontaneous cell death for some human tumors is thought to be a significant factor in limiting growth. However, the growth fraction, or percentage of cells in the cell cycle, is the most important determinant of overall tumor enlargement. The doubling times of human tumors have been estimated by direct measurement of chest radiographs of lesions or palpable masses to be 1 to 6 months.
The growth fraction indicates dividing cells that are potentially sensitive to chemotherapy; thus, it is not surprising that tumors with high growth fractions are the ones most easily curable by drugs. Among human tumors, only Burkitt's lymphoma and trophoblastic choriocarci-noma are readily curable by single-agent chemotherapy; both of these tumors have growth fractions close to 100%.
As tumors grow larger, the growth fraction within the tumor decreases, and the greater the distance of cells from nutrient blood vessels, the more likely they are to be in the G0-, or resting, phase. The growth fraction is less than 10% for slow-growing cancers of the colon or lung.
A number of factors must be considered before chemotherapy is instituted for a human cancer that has a low growth fraction. For instance, the larger the tumor, the more cells will be present in the nonproliferating, relatively resistant state. Therefore, the earlier chemotherapy is instituted, the greater the chance of a favorable response. Debulking of tumors by surgery or radiation therapy may be a means of stimulating the remaining cells into active proliferation. Small metastases may respond to drugs more dramatically than will large primary tumors or a larger metastasis in the same patient.
Several cycles of treatment may be necessary to achieve a substantial reduction in tumor size. The chemotherapeutic regimen, especially when one is dealing with large, solid tumors, probably should include agents that have cytotoxic activity against resting cells.
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