The Emperor of All Maladies: A Biography of Cancer (57 page)

But there was a pattern behind the deaths.
When the groups were analyzed by age
, women above fifty-five years had benefited from screening, with a reduction in breast cancer deaths by 20 percent. In younger women,
in contrast, screening with mammography showed no detectable benefit.

This pattern—a clearly discernible benefit for older women, and a barely detectable benefit in younger women—would be confirmed in scores of studies that followed Malmö.
In 2002, twenty-six years after the launch of the original
Malmö experiment, an exhaustive analysis combining all the
Swedish studies
was published in the
Lancet.
In all, 247,000 women had been enrolled in these trials. The pooled analysis vindicated the Malmö results. In aggregate, over the course of fifteen years, mammography had resulted in 20 to 30 percent reductions in breast cancer mortality for women aged fifty-five to seventy. But for women below fifty-five, the benefit was barely discernible.

Mammography, in short, was not going to be the unequivocal “savior” of all women with breast cancer.
Its effects, as the statistician Donald Berry describes it
, “are indisputable for a certain segment of women—but also indisputably modest in that segment.”
Berry wrote, “Screening is a lottery
. Any winnings are shared by the minority of women. . . . The overwhelming proportion of women experience no benefit and they pay with the time involved and the risks associated with screening. . . . The risk of not having a mammogram until after age 50 is about the same as riding a bicycle for 15 hours without a helmet.” If all women across the nation chose to ride helmetless for fifteen hours straight, there would surely be several more deaths than if they had all worn helmets. But for an individual woman who rides her bicycle helmetless to the corner grocery store once a week, the risk is so minor that some would dismiss it outright.

In Malmö, at least, this nuanced message has yet to sink in. Many women from the original mammographic cohort have died (of various causes), but mammography, as one Malmö resident described it, “is somewhat of a religion here.” On the windy winter morning that I stood outside the clinic, scores of women—some over fifty-five and some obviously younger—came in religiously for their annual X-rays. The clinic, I suspect, still ran with the same efficiency and diligence that had allowed it, after disastrous attempts in other cities, to rigorously complete one of the most seminal and difficult trials in the history of cancer prevention. Patients streamed in and out effortlessly, almost as if running an afternoon errand. Many of them rode off on their bicycles—oblivious of Berry’s warnings—without helmets.

Why did a simple, reproducible, inexpensive, easily learned technique—an X-ray image to detect the shadow of a small tumor in the breast—have to struggle for five decades and through nine trials before any benefit could be ascribed to it?

Part of the answer lies in the complexity of running early-detection trials, which are inherently slippery, contentious, and prone to error. Edinburgh was undone by flawed randomization; the BCDDP by nonrandomization. Shapiro’s trial was foiled by a faulty desire to be dispassionate; the Canadian trial by a flawed impulse to be compassionate.

Part of the answer lies also in the old conundrum of over- and underdiagnosis—although with an important twist. A mammogram, it turns out, is not a particularly good tool for detecting early breast cancer. Its false-positive and false-negative rates make it far from an ideal screening test. But the fatal flaw in mammography lies in that these rates are not absolute:
they depend on age
. For women above fifty-five, the incidence of breast cancer is high enough that even a relatively poor screening tool can detect an early tumor and provide a survival benefit. For women between forty and fifty years, though, the incidence of breast cancer sinks to a point that a “mass” detected on a mammogram, more often than not, turns out to be a false positive. To use a visual analogy: a magnifying lens designed to make small script legible does perfectly well when the font size is ten or even six points. But then it hits a limit. At a certain size font, chances of reading a letter correctly become about the same as reading a letter incorrectly. In women above fifty-five, where the “font size” of breast cancer incidence is large enough, a mammogram performs adequately. But in women between forty and fifty, the mammogram begins to squint at an uncomfortable threshold—exceeding its inherent capacity to become a discriminating test. No matter how intensively we test mammography in this group of women, it will always be a poor screening tool.

But the last part of the answer lies, surely, in how we imagine cancer and screening. We are a visual species. Seeing is believing, and to see cancer in its early, incipient form, we believe, must be the best way to prevent it. As the writer Malcolm Gladwell once described it, “
This is a textbook example
of how the battle against cancer is supposed to work. Use a powerful camera. Take a detailed picture. Spot the tumor as early as possible. Treat it immediately and aggressively. . . . The danger posed by a tumor is represented visually. Large is bad; small is better.”

But powerful as the camera might be, cancer confounds this simple
rule. Since metastasis is what kills patients with breast cancer, it is, of course, generally true that the ability to detect and remove premetastatic tumors saves women’s lives. But it is also true that just because a tumor is small does not mean that it is premetastatic. Even relatively small tumors barely detectable by mammography can carry genetic programs that make them vastly more likely to metastasize early. Conversely, large tumors may inherently be genetically benign—unlikely to invade and metastasize. Size matters, in other words—but only to a point. The difference in the behavior of tumors is not just a consequence of quantitative growth, but of qualitative growth.

A static picture cannot capture this qualitative growth. Seeing a “small” tumor and extracting it from the body does not guarantee our freedom from cancer—a fact that we still struggle to believe. In the end, a mammogram or a Pap smear is a portrait of cancer in its infancy. Like any portrait, it is drawn in the hopes that it might capture something essential about the subject—its psyche, its inner being, its future, its
behavior
. “
All photographs are accurate
,” the artist Richard Avedon liked to say, “[but] none of them is the truth.”

But if the “truth” of every cancer is imprinted in its behavior, then how might one capture this mysterious quality? How could scientists make that crucial transition between simply visualizing cancer and knowing its malignant potential, its vulnerabilities, its patterns of spread—its future?

By the late 1980s, the entire discipline of cancer prevention appeared to have stalled at this critical juncture. The missing element in the puzzle was a deeper understanding of carcinogenesis—a
mechanistic
understanding that would explain the means by which normal cells become cancer cells. Chronic inflammation with hepatitis B virus and
H. pylori
initiated the march of carcinogenesis, but by what route? The Ames test proved that mutagenicity was linked to carcinogenicity, but mutations in which genes, and by what mechanism?

And if such mutations were known, could they be used to launch more intelligent efforts to prevent cancer? Instead of running larger trials of mammography, for instance, could one run smarter trials of mammography—by risk-stratifying women (identifying those with predisposing mutations for breast cancer) such that high-risk women received higher levels of surveillance? Would that strategy, coupled with better technol
ogy, capture the identity of cancer more accurately than a simple, static portrait?

Cancer therapeutics, too, had seemingly arrived at the same bottleneck. Huggins and Walpole had shown that knowing the inner machinery of the cancer cell could reveal unique vulnerabilities. But the discovery had to come from the bottom up—
from
the cancer cell
to
its therapy. “
As the decade ended,” Bruce Chabner
, former director of the NCI’s Division of Cancer Treatment, recalled, “it was as if the whole discipline of oncology, both prevention and cure, had bumped up against a fundamental limitation of knowledge. We were trying to combat cancer without understanding the cancer cell, which was like launching rockets without understanding the internal combustion engine.”

But others disagreed. With screening tests still faltering, with carcinogens still at large, and with the mechanistic understanding of cancer in its infancy, the impatience to deploy a large-scale therapeutic attack on cancer grew to its bristling tipping point. A chemotherapeutic poison was a poison was a poison, and one did not need to understand a cancer cell to poison it. So, just as a generation of radical surgeons had once shuttered the blinds around itself and pushed the discipline to its terrifying limits, so, too, did a generation of radical chemotherapists. If every dividing cell in the body needed to be obliterated to rid it of cancer, then so be it. It was a conviction that would draw oncology into its darkest hour.

*
In addition to mammography, women also received a breast exam, typically performed by a surgeon.

Then did I beat them
as small as the dust of the earth, I did stamp them as the mire of the street, and did spread them abroad.

—Samuel 22:43

Cancer therapy is like beating the dog
with a stick to get rid of his fleas.

—Anna Deavere Smith,
Let Me Down Easy

February was my cruelest month. The second month of 2004 arrived with a salvo of deaths and relapses, each marked with the astonishing, punctuated clarity of a gunshot in winter. Steve Harmon, thirty-six, had esophageal cancer growing at the inlet of his stomach. For six months, he had soldiered through chemotherapy as if caught in a mythical punishment cycle devised by the Greeks. He was debilitated by perhaps the severest forms of nausea that I had ever encountered in a patient, but he had to keep eating to avoid losing weight. As the tumor whittled him down week by week, he became fixated, absurdly, on the measurement of his weight down to a fraction of an ounce, as if gripped by the fear that he might vanish altogether by reaching zero.

Meanwhile, a growing retinue of family members accompanied him to his clinic visits: three children who came with games and books and watched, unbearably, as their father shook with chills one morning; a brother who hovered suspiciously, then accusingly, as we shuffled and reshuffled medicines to keep Steve from throwing up; a wife who bravely shepherded the entire retinue through the whole affair as if it were a family trip gone horribly wrong.

One morning, finding Steve alone on one of the reclining chairs of the infusion room, I asked him whether he would rather have the chemotherapy alone, in a private room. Was it, perhaps, too much for his family—
for his children?

He looked away with a flicker of irritation. “I know what the statistics are.” His voice was strained, as if tightening against a harness. “Left to myself, I would not even try. I’m doing this
because
of the kids.”