Radiation and drug resistance of breast cancer.

There are clinical data correlating the control rates of adenocarcinoma of the breast with doses of irradiation and the volume of cancer. As the volume of cancer increases, doses have to be increased to obtain significant control rates. Of particular interest is subclinical disease, i.e., occult aggregates of cancer cells that cannot be palpated in areas accessible to palpation. Almost 100% of subclinical disease can be controlled with 4,500-5,000 rad in elective irradiation of clinically uninvolved lymphatics, whereas gross masses in excess of 5 cm in diameter require doses of 8,000-10,000 rad. The radiobiological explanations for these differences are 1) the randomness of cell killing, 2) hypoxia, and 3) repopulation. Using the same methodology of survival fractions there are now experimental data showing that resistance to drugs is a function of the number of clonogens and that hypoxic cells are also more resistant to drugs. Using the spheroid technique, it has been shown that cells centrally located in a spheroid are not affected by the drugs. Therefore, there is also a mechanical reason for drug resistance. In the last few years it has been postulated that mutations in the tumor cell population render some cells resistant to certain drugs. The often made statement that the development of permanent resistance more precisely accounts for the greater effectiveness of combination chemotherapy over single agents is discussed in the light of data from clinical trials.