Does Screening Mammography Work?

The American Cancer Society (ACS) urges women 40 and older to have annual mammograms. "Mammography is especially valuable as an early detection tool because it can identify breast abnormalities that may be cancer at an early stage," writes the ACS in Cancer Facts and Figures 2001. "Numerous studies have shown that early detection saves lives and increases treatment options. The declines in breast cancer mortality have been attributed, in large part, to the use of regular screening mammography." Supposedly, these recommendations are based on extensive randomized controlled trials (RCTs) showing that mammography extends lives.

Now, however, Ole Olsen and Peter C. Gøtzsche of the Nordic Cochrane Collaboration, Copenhagen, have taken an independent look at the data supporting the use of screening mammography and found it lacking {Lancet 2001;358:1340-1342 Their full report is available online at http://image.thelancet.com/lancet/extra/fullreport.pdf}.There is simply no reliable evidence, they write, that screening mammography actually reduces deaths among women who receive it. "Mammographic screening is of uncertain benefit, they write, "and leads to greater use of more aggressive treatment. By detecting cancers early, mammographic screening is widely believed to lead to reduced mortality from breast cancer and to less aggressive treatment." But their review "failed to find a decrease in overall mortality, and the best trials also failed to find a reduction in breast cancer mortality. In fact, screening leads to more aggressive treatment," not to "increased treatment options," as the ACS contends.

If you look in the cancer textbooks, not to mention innumerable websites, you will find vigorous recommendations for screening mammography. So how did these two authors reach such conclusions so at variance with accepted opinion? They carefully scrutinized the quality of each of the RCTs that allegedly proves the value of mammography. Were the patients in the two arms comparable at the start? Were they properly randomized? Was there an unbiased assessment of the outcome of the trials?

On the basis of such detailed assessments, they classify clinical trials into four groups: high quality, medium, poor and flawed. Of the seven existing randomized trials of screening mammography, none in their opinion was of high quality, two were of medium quality (those from Malmö and Canada), three were of poor quality (Two-County, Stockholm, and Göteborg) and two were flawed (New York and Edinburgh).

One of the problems they uncovered was that if a patient died in the control group her death was more likely to be ascribed to breast cancer than similar patients in the treated group. This made the outcome in untreated patients appear worse than it necessarily was.

One danger of mammography, they say, is that screened women are more likely to receive radiation therapy than unscreened women. Radiation, they write, "is expected to increase overall mortality because of cardiovascular adverse effects. These deaths were not counted as deaths related to screening in the trials we assessed." In other words, if a woman gets screened, she is more likely to be diagnosed with breast cancer. If she is diagnosed with breast cancer, she is likely to get adjuvant radiation therapy. But because of that she is at greater risk of damage to her cardiovascular system {Lancet 2000;355:1757-70}.

The main outcome measured in screening trials is the chance that a woman will die of breast cancer. But this ignores the likelihood of other causes of death. The authors consider more meaningful the data on overall mortality. In the two trials with the best methodology, there was no difference in the relative overall risk of death between those who received mammograms and those who didn't. In the Swedish trial, there was originally an imbalance in the ages of participants. When these were adjusted the benefit of mammography evaporated. Olsen and Gøtzsche conclude: "The reliable evidence does not indicate any survival benefit of mass screening for breast cancer."

How, then, can the utility of screening mammography be justified? While the best trials failed to find an effect, those trials with poor-quality data "found a marked difference." Thus, advocates have relied on faulty data to reach erroneous conclusions. But results from different quality groups "should not be combined," the authors caution.

They state that screening leads to more aggressive treatment, increasing the number of breast operations by up to 30 percent. The reason for this increase is that "screening identifies some slow-growing tumors that would never have developed into cancer in the women's remaining lifetimes, as well as cell changes that are histologically cancer but biologically benign." Furthermore, more accurate mammography could lead to "additional overtreatment," because of the detection of even more early and questionable lesions. "The problem cannot be avoided," they add.

Gøtsche and Olsen have thus re-opened the question of mammography's utility and safety. As you might expect, an extraordinary battle is shaping up around their findings. It has led to a serious division within the Cochrane Collaboration, an international organization devoted to rigorous and systematic reviews of clinical trials. This collaboration has "broken down badly," wrote Richard Horton, MD, editor of the Lancet. Certain Cochrane editors added statements to Gøtzsche and Olsen's analysis "which lent support to arguments in favor of screening and excluded data about the effects of screening on subsequent treatment" This outrageous behavior "erodes the academic freedom of these investigators," said Horton.

Where does this leave screening mammography? Some people will argue that today's mammography techniques are so far superior to the older techniques that historical data is simply not applicable. This sort of argument is often produced when clinical trials do not confirm one's theories! It simply makes the refutation of any evolving treatment impossible. Besides, as Richard Horton notes, "women should not be expected to forgive old-and disproven-screening practices" {Lancet 2001;358:1284-5}.

Does this mean that no woman should have a mammogram? Not at all. Each case must be considered on its own merits. But it does point to the weaknesses in the arguments currently being mustered on behalf of mammography screening of huge populations. New, less invasive (and, we might add, less painful) techniques are desperately needed. And further clinical trials need to be done to see if, using the most modern equipment and techniques, all-cause mortality can be reduced by screening mammography.

Adjuvant Radiation for Rectal Cancer?

In the same issue of the Lancet there is a meta-analysis of adjuvant radiation therapy for rectal cancer {Lancet 2001;358:1291-1304}. The authors (from the international Colorectal Cancer Collaborative Group) analyzed the results in 8,507 patients from 22 randomized trials. These results clearly show that neither pre- or postoperative radiation therapy has any appreciable effect on overall survival in patients with rectal cancer.

Overall survival at ten years was 26.9 percent in those who received some form of radiation therapy compared to 25.3 percent in those who did not. Survival was not significantly affected by whether the radiation was given pre- or post-surgery.

Preoperative radiation therapy did decrease the chance of a recurrence at five years by 7 percentage points: 45.9 percent compared to 52.9 percent. The results tended to be more significant in those trials that gave what is called a "biologically effective dose" of at least 30 Grays (Gy).

Patients who received postoperative radiation therapy had a 9 percent lower risk of death from rectal cancer than controls. But this survival advantage is all but wiped out by the more frequent deaths from other causes in the radiation therapy group. To quote the study, "The reduction in deaths from rectal cancers in patients who had radiotherapy was partly counterbalanced by an increase in death from other causes." This is a pattern that is seen in many other kinds of cancers as well.

Overall, the risk of death from causes other than rectal cancer was 15 percent higher in those who received radiation therapy than in those who did not. This was statistically significant. Almost all of these excess non-rectal cancer deaths occurred in the first year. Most were due to cardiovascular disease and infections. Patients who received radiation therapy were also more likely to die of surgical complications or from "unknown causes." In fact, there was one death from causes unrelated to rectal cancer for every 21 patients who were irradiated, with older people especially at risk.

The authors clearly state that "there was no clear benefit of radiotherapy in respect of overall survival." The differences were "practically negligible," said Bruce D. Minsky, MD, a radiation therapist at Memorial Sloan-Kettering Cancer Center, in an accompanying editorial {Lancet 2001;358:1286}.

So is radiation therapy for rectal cancer finished? Not in the least. In fact, Dr. Minsky believes that these results "give support to adjuvant radiotherapy for rectal cancer." How is that possible? Because radiation somewhat decreases the likelihood of a recurrence. As the article's authors explain: "Uncontrolled local recurrence can have a devastating effect on a patient's quality of life and so improved local control with radiotherapy might be a sufficient benefit to justify its use."

Yes, uncontrolled local recurrences are devastating. But so too are excess deaths caused by radiation therapy, such as cardiovascular disease, pneumonia and other infections, and those mysterious injuries that masquerade as "death by unknown causes."

In addition, neither article nor editorial mentions that the side effects of radiation therapy to the bowel can be devastating to quality of life. Diarrhea, bleeding, tenesmus (a painful spasm of the anal sphincter), and pain on defecation are frequent during therapy (even at 15-20 Gy, not the 30 Gy that is advocated in the article).

These symptoms commonly subside when treatment stops. But six months to a year later, delayed post-radiation symptoms may then develop. Here is an abbreviated description of these symptoms from a recent textbook: "There may be two to four or even eight or more bowel movements a day, and the urgency may be compelling. Blood is also often seen. Tenesmus is frequent, and cramping pain is often associated with defecation. Radiation proctitis frequently is associated with pain and bleeding; the latter may be severe and persistent, occasionally requiring transfusionsSevere or complete obstruction may develop" {Fajardo LF, et al. Radiation Pathology, Oxford, 2001: 244-245}.

Any evaluation of radiation therapy must take into effect not just the statistical effect of treatment on recurrences, but what actual patients experience as a result of the therapy. What patients and their families need is the complete picture, without which it is impossible for them to make educated decisions. But how many patients, we wonder, strongly urged to take adjuvant radiation therapy, are told that radiation has not been proven to extend life but may in fact cause serious short and long-term adverse effects? How many are told that adjuvant radiation may in fact cause their untimely death?

Whatever Happened to Endostatin and Angiostatin?

You may remember how almost four years ago, the New York Times proclaimed the imminent cure for cancer. Judah Folkman, MD of Harvard had propounded a theory that tumors could be arrested by preventing new blood vessel growth, a process he dubbed "angiogenesis inhibition." The Times proclaimed: "Within a year, if all goes well, the first cancer patient will be injected with two new drugs that can eradicate any type of cancer, with no obvious side effects and no drug resistance--in mice." So, how well have the first such drugs fared in human clinical trials?

At the 2001 meeting of the American Society of Clinical Oncology (ASCO), researchers presented their first data using two of Dr. Folkman's proposed drugs, Endostatin and Angiostatin. In Boston, 19 patients were treated. Twelve had to be removed from the study due to disease progression, while 6 others withdrew voluntarily. That left a single patient with "stable disease" who was still receiving treatment {ASCO 2001 Meeting Abstract #275}. There were no responses (measurable shrinkage of tumor).

In another phase I study, scientists at M.D. Anderson Cancer Center, Houston, reported that a single patient out of 22 remained in the study at one year; another patient had some minor evidence of anti-tumor activity {ASCO 2001 Meeting Abstract #9}.

At the same meeting, Philadelphia scientists reported on a phase I trial of Angiostatin. It was given to 15 patients. There were reductions in biochemical markers in some patients. However, they did not report any clinical results {ASCO 2001 Meeting Abstract #10}.

Overall, results with Endostatin and Angiostatin have been disappointing. There was little or no clinical benefit from these treatments. There were none of the dramatic responses, much less cures, that were dangled before the public by the media four years ago.

--Ralph W. Moss, Ph.D.