The practice of medicine is often far from straightforward, and simple logic can mislead. For example, elevated values of the widely used Prostate-Specific Antigen, or PSA, blood test are considered an early indicator of prostate cancer and, used for screening, can detect small, early cancers. However, false positives are not infrequent. Also, discovering and treating a small tumor often does not reduce the chance of dying from prostate cancer because many tumors found through PSA testing grow so slowly that they are unlikely to be life threatening and do not require surgery. Therefore, far fewer operations are done now than in the past, and we are able to avoid the cure being worse than the disease.
Even the results of clinical studies can be counter-intuitive and offer a lesson in not making unfounded assumptions. I encountered an example recently in a journal article about a long-term study of the benefits of post-surgery radiation for breast cancer.
Radiotherapy after breast-conserving surgery for early breast cancer substantially reduced the risk of disease recurrence, but – and here’s the surprising part -- the benefit did not translate to an improvement in overall survival (OS) after 30-year follow-up.
Here’s how the study, the epic 30-year Scottish breast conservation trial, was conducted: From 1985 to 1991, it enrolled 585 patients ages 70 and younger with primary breast tumors. After local excision of the tumor (with a safety margin of one centimeter) and an axillary lymph node biopsy or clearance, all patients received systemic therapy with oral or intravenous drugs appropriate to the estrogen receptor status of their tumor. (Different drugs are indicated depending on the genetics of the tumor.)
The patients were then randomized to either adjuvant radiotherapy or to no radiotherapy, which was the fundamental variable in the study -- and local recurrence (that is, the development of a new tumor in the same breast) and overall survival (OS) were followed over many years.
In the initial analysis of the trial at six years, the local recurrence rate was 5.8% in the radiotherapy arm and 24.5% in the no-radiotherapy arm, with no difference in OS.
At 10 years, local recurrence rates were 8.8% with radiotherapy versus 31% with no radiotherapy; at 20 years, rates were 15.2% and 37.6%, respectively, and at 30 years, rates were 27.8% and 42.7%.
Thus, the addition of radiotherapy to surgery and drug treatment significantly lowered the incidence of local recurrence of tumors, which is not surprising. Perhaps unexpected, however, was the finding that by the 30-year mark, there was no significant difference in overall survival (OS) between patients who received radiotherapy and those who did not: OS rates were 72.5% and 70.8%, respectively, at 10 years; 48.6% and 48.4% at 20 years; and 23.7% and 27.5% -- in other words, statistically indistinguishable.
If radiotherapy lowers the incidence of recurrence of cancer in the affected breast, and therefore, presumably the possibility of resulting metastasis and mortality, why is long-term survival not also enhanced?
To answer that question, I consulted Dr. Joel E. Tepper, an eminent academic radiation oncologist at the University of North Carolina, Chapel Hill. He explained that there are two reasons:
The first, and probably the most important, is that local recurrences can be well treated with a mastectomy in most patients, especially if the patients are carefully followed. The second is that (especially with older techniques) there is likely some mortality from the extra treatment, specifically late cardiac injury with old techniques for left sided breast cancer. If they analyzed right vs left, they might see a survival advantage in the right sided tumors with RT. This has been looked at in some other reports.
That second point is interesting, because it suggests that there were side effects of the radiotherapy that wiped out the possible overall survival advantage of the treatment.
Dr. Tepper’s explanation also serves as reminder that we constantly study the safety and effectiveness of various drug, surgery, and radiotherapy regimens in order to find out how effective they are and how they might be improved. The impressive advances in radiotherapy to treat cancer in recent decades, for example, are discussed here.
Medicine, like the science that underlies it, is seldom transformed by “Eureka” breakthroughs; rather, it is most often a process of systematically accumulating knowledge and making incremental improvements.
Henry I. Miller, MS, MD
Henry I. Miller, MS, MD, is the Glenn Swogger Distinguished Fellow at the American Council on Science and Health. His research focuses on public policy toward science, technology, and medicine, encompassing a number of areas, including pharmaceutical development, genetic engineering, models for regulatory reform, precision medicine, and the emergence of new viral diseases. Dr. Miller served for fifteen years at the US Food and Drug Administration (FDA) in a number of posts, including as the founding director of the Office of Biotechnology.
