“Insignificant” Cancer?
What Should You Do?

Twenty years ago, most men diagnosed with prostate cancer had advanced disease. Only about 25 percent of men were diagnosed with cancer that appeared to be confined within the prostate—and of those, only about half actually had curable disease. Today, the story is nearly reversed: 75 percent of men diagnosed with prostate cancer have clinically localized disease, and at least 80 percent of them are curable.

PSA testing has been a godsend for men with prostate cancer. It’s been hugely successful at spotting cancer in its earliest, most curable stages. However, as with every other screening test (with breast cancer, for example), as cancers are detected earlier than ever, some are detected at such an early stage, and are so small and slow-growing, that they don’t need to be treated.

Today, some men are found to have minuscule amounts of cancer—smaller than 0.2 cubic centimeters, about the size of a pinpoint, captured by sheer chance during a biopsy. For some men, these are cancers that will never cause harm, and ideally, should never have been diagnosed. Which leads to a treatment dilemma: If this kind of small-volume cancer is diagnosed, what should happen? To treat, or not to treat? What should a man do?

This is the kind of problem urologists —who, for so many years, could only diagnose prostate cancer when the chance of cure had become uncertain—have always dreamed of having. It’s also, increasingly, a clinical challenge. Exactly which kind of cancer is it—the “good” kind, that seems content to remain in the prostate and never causes harm, or the kind that will be less indolent over time, and needs to be nipped in the bud? “To what extent are we diagnosing and treating a disease that would progress very slowly, and never threaten a man’s life?” asks urologist H. Ballentine Carter, M.D., who is also a professor of oncology at the Kimmel Cancer Center. “For which men is surgery necessary, and which men can safely forego treatment?”

Fortunately, there are guidelines, developed by Jonathan Epstein, M.D., Rose-Lee and Keith Reinhard Professor of Urologic Pathology (see Epstein’s criteria). There’s also the matter of a man’s age, Carter notes. “In a very young man (in his thirties, forties or fifties), a very small tumor might be significant. But in an older man, a very small tumor probably isn’t significant, because of the time it takes for that tumor to grow and become dangerous.” Even without treatment, cancer that is fairly well-differentiated (to the pathologist, this kind of cancer cell looks fairly normal, or not terribly abnormal) Gleason 6 or below, and localized to the prostate, takes more than 10 years to spread and cause harm.

Thus, “for men who are in their sixties or older, we feel that if we can identify who has low-volume disease, then expectant management may well be a rational approach.” For the last few years, Carter and Epstein have been studying this strategy in men with stage T1c disease. Their results, published in the Journal of Urology with Patrick C. Walsh, M.D., and Patricia Landis, were so encouraging that a larger trial, involving several institutions, is in the works.

In this study, 81 men who fulfilled the criteria for low-volume disease were followed. At an average of two years’ followup, 25 (31 percent) had progression of disease. In 22 of these men, every followup biopsy showed cancer. In the men who had progression of cancer, PSA density was significantly higher, and free PSA was lower. Thirteen of these men underwent radical prostatectomy, and 12 (92 percent) had curable disease.

Most importantly, Epstein says, the Hopkins research shows that “there is no evidence that prostate cancer grade worsens significantly during a one and a half-to two-year period after biopsy. If a tumor grade changes relatively soon after biopsy, it’s most likely not because the tumor evolved, but because the higher grade component of the cancer was missed.” Based on this study, what should men do? “If a man is interested in this approach, the first thing we do is have his pathology slides re-read here at Hopkins (by Epstein), and if we think he is still a candidate, we repeat the biopsy, taking at least 12 samples,” says Carter.

Then, if the repeat biopsy confirms that the cancer is low-volume, the man returns to Hopkins every six months for a PSA test and rectal exam, and undergoes a follow- up biopsy once a year. Epstein has found that if the repeat biopsy is negative, it almost certainly means that the cancer truly tiny, and the initial biopsy just happened to hit some of its few cells. “An important message of this paper is that as we accumulate biopsy history on these men, and the biopsies continue to be negative, it’s more evidence that what was found initially was small-volume disease,” he says. The study has now expanded to include more than 200 men. “Another thing we’ve learned,” notes Carter, “is that there’s a lot of variability in men’s comfort levels. Some men end up getting treated, even though there is no evidence of serious cancer, because they learn something about themselves—they don’t like the uncertainty. They worry, and that decreases their quality of life. Then there are other men who appear to be incredibly comfortable with this approach, and for them, it’s the best decision.”

Carter and Epstein point out that these results are short-term, because the entity of T1c cancer has been recognized for less than a decade. “Because the follow-up is short-term, we can’t say that this is an absolutely safe approach,” says Carter. “We think it is, but we’re still trying to learn. What we do know is that the potential here is very exciting, because we may save a lot of men from surgery that they don’t need.”