In patients, substantial drug effects, approaching cure, have been observed in acute lymphocytic leukemia, Hodgkin's disease, choriocarcinoma, Burkitt's tumor, and some childhood solid tumors. These are all rapidly growing tumors. The so-called solid tumors, such as cancers of the breast, lung, and colon, are less susceptible to drugs. These types of cancer are considerably slower in growth rates.
A major effort is being undertaken by the National Cancer Institute to search for new drugs effective against these common epithelial-derived cancers. In addition, the known drugs that are effective against the rapidly growing tumors may be effective against the slowly growing ones. However, the dosage schedules based on selective toxicity data for the rapid tumors are probably not suited to the slow ones.
Greatly intensified studies are focusing on the kinetics of the growth of solid tumors and the nature of the cell population in such tumors. One of the findings is that as a tumor grows larger the volume doubling time becomes longer and longer. The doubling time (or volume doubling time) is the time required for the viable tumor cell number to double, or the volume of the tumor to double. These values may be longer than the average generation, or cell cycle, time of the most actively dividing cells.
Very small tumors appear to grow rapidly, but for tumors of the size that is clinically apparent, the volume doubling time is measured in weeks. The time required for one tumor cell and its progeny to proliferate to the lethal number of 1012 may be measured in years.
An understanding of this phenomenon is important to decisions on scheduling of drug treatment. As an example, one of the possible reasons for the increased doubling time of solid tumors is that as the tumor gets older a certain fraction of the cells may crowd together, enter a non-proliferating pool, and stop dividing. Studies of slowly growing tumors in animals using radioactive-labeled compounds have shown that only about one percent of the tumor cells are proliferating.
This slowdown in proliferation may be due to decreased availability of nutrients, decreased availability of oxygen, poor blood supply, or increased waste products. A laboratory study has provided some evidence to confirm this idea. If in an experimental mouse or rat tumor that has reached the stage of long volume doubling time some bits of the tumor are transplanted into new animals, the tumor grows initially with a very short doubling time. This situation seems to indicate that in a tumor in which many cells are non-proliferating, they may be capable of resuming malignant growth under the proper circumstances.
Drugs such as methotrexate, an antimetabolite, that kill cells in one phase of the generation cycle, generally the S phase, are called cell cycle stage specific agents. Treatment of a tumor cell population that hypothetically has a large non-proliferating pool and a small proliferating pool with a cell cycle stage specific agent would kill the cells that are in active mitosis. This might relieve the crowding of cells in the tumor, free some of the available nutrients, and result in transition of some of the cells from the non-proliferating into the proliferating pool where they would be susceptible to the drug. Thus, control of a tumor might result from repeated courses of an antimetabolite at short intervals.
But suppose the long doubling time is due to a very long generation time; that is, the cells may all be in the generation cycle, but one phase of the cycle may have become very long. Then only a very small fraction at any one time would be in the S phase and susceptible to a cell cycle stage specific agent. It would be necessary to give the drug about half the time to destroy about half of the cells to keep the tumor under control. Unless half the tumor cells were killed in the time it would take for the tumor to double in size, the tumor would increase and grow even though the rate of growth would have been slowed.
An example of a plan for treatment of a patient, based on current knowledge of cell kinetics in terms of the growth of tumor cells and their peculiar sensitivities during certain phases of cell division might be the following: treat with antimetabolites to eradicate a high percentage of actively growing tumor cells; rest the patient, who now has a small body burden of tumor cells, long enough to give the bone marrow an opportunity to recover; treat with an alkylating agent, which is not a cell cycle specific agent and acts on all phases of rapidly dividing cells and also on some non-proliferating cells.
Research to ascertain the duration of the generation cycle and DNA synthesis in both normal and cancer tissues is one of the currently active areas. Other studies are attempting to correlate the predictive value of the model systems with the effectiveness of chemotherapy in patients.