Sometimes, the results of clinical studies are counter-intuitive and offer a lesson in not making unfounded assumptions. I encountered an example of that when I read a study on the benefits of radiation therapy after surgery 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 after 30-year follow-up.
The study was the epic 30-year Scottish breast conservation trial. From 1985 to 1991, it enrolled 585 patients 70 years old and younger with primary breast tumors. After local excision of the tumor 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 were followed.
In the initial analysis of the trial at six years, the local recurrence rate was 5.8 percent in the radiotherapy arm and 24.5 percent in the no-radiotherapy arm, with no difference in overall survival.
At 10 years, local recurrence rates were 8.8 percent with radiotherapy versus 31 percent with no radiotherapy; at 20 years, rates were 15.2 percent and 37.6 percent, respectively; and at 30 years, rates were 27.8 percent and 42.7 percent.
Thus, adding radiotherapy to surgery and drug treatment 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 between patients who received radiotherapy and those who did not. Overall survival rates were 72.5 percent and 70.8 percent, respectively, at 10 years; 48.6 percent and 48.4 percent at 20 years; and 23.7 percent and 27.5 percent — 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 Tepper, an eminent academic radiation oncologist. 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 the older techniques that were used 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 the study revealed side effects of the radiotherapy that wiped out what could have been an overall survival advantage from the treatment.
Tepper’s explanation is a reminder that we perform these kinds of studies of various treatment regimens to find out how effective they are and how they might be improved. Medicine, like the science that underlies it, is seldom transformed by “Eureka” breakthroughs; instead, it is most often a process of systematically accumulating knowledge and making incremental improvements.