Understanding the Tumor Doubling Defense
The growth of a tumor mass inevitably results in the mass doubling in size over time. Experts defending delay in diagnosis of cancer cases have used this seemingly innocent and logically necessary, though irrelevant, observation over the last twenty years to lead juries to ignore common sense and find that the negligent failure to have earlier diagnosed cancer was meaningless because the death or morbidity was inevitable. It is the object of this article to examine this defense and demonstrate its fallibilities.
A primary tumor starts from a single cell. This first tumor cell multiplies geometrically over time. Assuming the cell and its progeny survive, the number of cells present increases by a factor of two, between generation from 1 to 2-4-8-16-32, and so forth.
In fact, the increase in the number of cells present in a given tumor depends on the percentage of cells proliferating, the cell cycle time of those cells that do proliferate and the fraction of tumor cells that do not survive. The net growth of the tumor volume will remain reasonably exponential only if one presumes that these factors remain constant.1 This presumption is demonstrably false with respect to metastases and at different parts of the growth cycle.
In virtually every trial where the tumor doubling time defense is raised, an exhibit in the form depicted in figure 1 is presented:
Such an exhibit hopes to persuade jurors to think of a very small tumor of, for example, .2 cm. to 1 cm. in diameter as having great malignant potential far out of proportion to its size. For example, a 1 cm. tumor contains 109 (1 billion) cells. Figure 1 presupposes that the tumor cells having a diameter of 10 µm require 32 cell divisions to acquire a 1 cubic cm. mass containing 109 cells. Note, that if one assumes the tumor cells are 25 µm in diameter, 26 doublings would be required to reach the same volume but would contain 1/64th as many cells or about 15,000,000 as opposed to 1,000,000,000.
Of course, the difference between 15,000,000 and 1,000,000,000 cells is not particularly relevant unless the number of cells present impacts upon the clinical treatment of the cancer and its prognosis, if earlier treated. As early as 1981, Spratt, a leading proponent of the tumor-doubling defense, urged that cancer therapy could make no difference once a tumor has reached 9 doublings.2 That is, Spratt would have a jury believe a tumor containing 512 cells had metastasized with unavoidable fatal consequences.
Whether one assumes that a cancer cell is 10 µm or 25 µm in diameter, it is easy to see that even at 14 doublings (a more generous number suggested by Spratt), breast cancer would be invisible to mammography. If Spratt’s analysis were correct, by the time a cancer diagnosis can be made, effective treatment can no longer be provided. However, no one, including Spratt, has proven in general or in any specific case that the metastasis that kills the patient occurred before 14 doublings or that even if metastasis had occurred, that early treatment would not have been helpful. Cancers, if untreated, eventually kill, either because they interfere with organ function or because cancer tissue competes with normal tissues for nutrients. Eventually, because cancer cells proliferate indefinitely, their number daily multiplying, cancer cells will demand a critical portion of nutrients available to the body as a whole. This critical amount is known as lethal tumor burden. The lethal burden in most patients is reached at 1012 to 1013 cells, a tumor volume containing between 1,000 and 10,000 times the number of cells present after 32 doublings. Often the argument is made that, at 32 doublings (a time when a tumor may weigh as little as 1 gram and is pea-sized), the tumor is nearing its biological end. Plaintiffs’ lawyers should remember, however, that during the short remaining life of that same tumor, it would undergo a 1,000 to 10,000-fold enlargement. It takes two-thirds of its life to reach 1/1000th to 1/10,000th of its lethal volume.
Put more simply, a tumor takes two-thirds of its life to go from something much smaller than a grain of sand to something slightly larger than a pea. Yet, the jury is urged to believe that the metastatic potential of this pea must be great because it contains 1,000,000,000 cells. This deception is facilitated by showing that the further growth of the tumor to its lethal volume occurs in a short period of time. Figure one is an example of an illustration seen at trial. The size of the tumor and number of cells required to reach its lethal burden is not depicted. In fact, a mass representative of lethal tumor volume should be just under 5 inches in diameter and contain 1012cells. The pea-sized mass is in fact a trivial part of the ultimate growth of the tumor to its lethal potential containing 1000 times as many cells. A juror, given the opportunity, is not likely to believe a grain of sand has the malignant potential of a golf ball-sized mass containing 10,000 times as many cells. Proponents of the tumor-doubling defense succeed if they can avoid such common sense comparisons.
The assertion that fatal metastasis has always occurred before the tumor can be detected is sheer speculation and is readily disproven by the remarkable cure rates for diseases such as cervical cancer, which remains eminently curable even after invasive cancer has developed.
One novel and unscientific defense advocated by Ostrum and others is to argue from the size of tumor at the time of diagnosis that the tumor at the time that the earlier diagnosis should have been made would have been of such a size as would have already metastasized. This argument depends upon the earlier false premise that growth of a given tumor is exponential and predictable. However, it is important to remember that this argument also depends upon accurate measurement of the tumor at diagnosis. The measurement of tumor size on a mammogram is often impossible. In addition, when tumors are examined carefully under the microscope there is sometimes much more inflammatory tissue than malignant cells and assessment of tumor cell density is therefore an important factor in understanding this defense. The fewer malignant cells present within the measured tumor mass the later the critical metastatic event(s).
Prolonged survival, whether or not the patient has been cured, is hardly an insignificant benefit of early diagnosis. Disease-free survival prolonged to the point of a person reaching their normal life expectancy certainly represents a cure in any layman’s definition. The possibility of such survival exists for all forms of the cancer when early diagnosis is provided. The chances of prolonging survival with early diagnosis and treatment is virtually certain. Even if one assumes that metastasis has already occurred at the time that a primary tumor is removed, it cannot be seriously questioned that the primary tumor contributed to the overall tumor burden. New tumor needs time to grow sufficiently to replace the cells that have been removed. How quickly depends not only on tumor-doubling time, but also on the impact upon the residual tumor burden of the body’s immune defenses and on the success of any adjuvant therapy that may be employed in the patient’s care. Adjuvant chemotherapy is successful even where it only wipes out 95% to 99.9% of residual cancer cells in a patient’s body. Presumably, in those patients who are not cured by adjuvant therapy, the remaining tumor cells are resistant to chemotherapy. Yet, even applying Spratt’s median doubling time of 260 days where reduction of the metastatic tumor from 1,000,000 to 10,000 cells has occurred, 6-2/3 cell generations are required for the tumor to grow back to 1,000,000 cells. With a doubling time of 260 days, a patient wouldn’t reach his/her lethal tumor burden for many years (lethal tumor burden of 1012 is reached after 40 to 45 tumor doublings).3
Moreover, if adjuvant therapy can destroy 99.9% of residual tumor burden at some point and if chemotherapy is more effective at smaller tumor burdens, one can reasonably conclude that at some point, even after metastasis, 100% of metastatic cells can be eliminated. Consider the patient with recurrent cancer who is administered chemotherapy and enjoys visible shrinkage of tumor mass. Given the limitations of cumulative chemotherapeutic dose (only so much can be given), the only way to eliminate the recurrent cancer is to reduce the tumor burden at the outset. Even if the tumor cannot be eliminated, the benefit of that time required for the tumor to resume its pre-treatment volume cannot be ignored. It is not for the wrongdoer to raise conjecture concerning the magnitude of those chances that he has by his wrongful conduct placed beyond the possibility of realization.4
The assumption that in all cancers there exists the possibility that metastasis has occurred before diagnosis and removal of the primary tumor is the basis for adjuvant chemotherapy. But even those who believe that metastasis has occurred prior to diagnosis and removal must concede that the size of occult metastases at the time of treatment of the primary tumor and before adjuvant chemotherapy is significant. Adjuvant chemotherapy is known to be less effective when tumor burdens are high.5
Prior to the development of a surgical treatment for cancer in the 1800’s, women died of breast cancer because of hemorrhage within the primary breast tumor and/or infections. Now effective treatment exists for most forms of cancer if treated early. When a medical malpractice defendant attempts to prove otherwise, it is our responsibility to recognize and expose the invalidity of such arguments. By so doing, we free juries to use their collective common sense and intuition and reach the same conclusions that are the basis of 21st century medical practice in the diagnosis and treatment of cancer.
1 Friberg, S., Mattson, S., On the Growth Rates of Human Malignant Tumor, Implications for Medical Decision Making, J. Surg. Oncol. 1997 Aug; 65(4): 284-97.
2 Spratt, J.S., The Relationship Between Rates of Growth of Cancers and The Intervals Between the Screening Exams Necessary for Detection, Cancer Detection Prev., 1981:4(1-4).
3 Friberg, supra.
4 Hamil v. Bashline, 481 Pa 256, 392 A2d 1280 (1978).
5 Steel, G.G., Cell Loss As a Factor in the Growth Rate of Human Tumours, Eur J. Cancer, 1967; 3: 381-7.